Obstructive sleep apnea treatment devices, systems and methods

ABSTRACT

A method of treating a patient, comprising: sensing a biological parameter indicative of respiration; analyzing the biological parameter to identify a respiratory cycle; identifying an inspiratory phase of the respiratory cycle; and delivering stimulation to a hypoglossal nerve of the patient, wherein stimulation is delivered if a duration of the inspiratory phase of the respiratory cycle is greater than a predetermined portion of a duration of the entire respiratory cycle.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/178,104, filed Feb. 11, 2014, now U.S. Pat. No. 9,186,511, which is acontinuation-in-part application of U.S. application Ser. No.12/835,984, filed Jul. 14, 2010, now abandoned, which is a continuationof U.S. application Ser. No. 11/907,532, filed Oct. 12, 2007, now U.S.Pat. No. 7,809,442, which claims the benefits of priority to U.S.Provisional Patent Application Nos. 60/851,386, filed Oct. 13, 2006, and60/918,257, filed Mar. 14, 2007. Application Ser. No. 14/178,104 is alsoa continuation-in-part application of U.S. application Ser. No.12/650,045, filed Dec. 30, 2009, now U.S. Pat. No. 9,744,354, whichclaims the benefits of priority to U.S. Provisional Patent ApplicationNo. 61/204,008, filed Dec. 31, 2008. Application Ser. No. 14/178,104 isalso a continuation-in-part of U.S. application Ser. No. 13/106,460,filed May 12, 2011, now U.S. Pat. No. 9,913,982, which claims thebenefits of priority to U.S. Provisional Patent Application No.61/437,573, filed Jan. 28, 2011. Application Ser. No. 14/178,104 is alsoa continuation-in-part of U.S. application Ser. No. 13/205,315, filedAug. 8, 2011, now U.S. Pat. No. 8,855,771, which is a continuation ofU.S. application Ser. No. 13/113,524, filed May 23, 2011, now abandoned,which claims the benefits of priority to U.S. Provisional PatentApplication Nos. 61/467,758, filed Mar. 25, 2011, and 61/437,573, filedJan. 28, 2011. Application Ser. No. 14/178,104 is also acontinuation-in-part of U.S. application Ser. No. 13/633,670, filed Oct.2, 2012, now U.S. Pat. No. 9,205,262, which claims the benefits ofpriority to U.S. Provisional Patent Application No. 61/542,617, filedOct. 3, 2011. Application Ser. No. 14/178,104 is also related to U.S.application Ser. No. 11/907,533, filed Oct. 12, 2007, now U.S. Pat. No.8,417,343, which claims the benefits of priority to U.S. ProvisionalPatent Application Nos. 60/851,386, filed Oct. 13, 2006, and 60/918,257,filed Mar. 14, 2007. Each of the aforementioned applications isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The embodiments described herein relate to devices, systems andassociated methods for treating sleeping disorders. More particularly,the embodiments described herein relate to devices, systems and methodsfor treating obstructive sleep apnea.

The embodiments described herein relate to devices, systems andassociated methods for treating sleep disordered breathing. Moreparticularly, the embodiments described herein relate to devices,systems and methods for treating obstructive sleep apnea.

The embodiments described herein relate, for example, to devices andmethods for modifying tissue of the upper airway for the treat ofobstructive sleep apnea and snoring.

BACKGROUND OF THE INVENTION

Obstructive sleep apnea (OSA) is highly prevalent, affecting one in fiveadults in the United States. One in fifteen adults has moderate tosevere OSA requiring treatment. Untreated OSA results in reduced qualityof life measures and increased risk of disease including hypertension,stroke, heart disease, etc.

Continuous positive airway pressure (CPAP) is a standard treatment forOSA. While CPAP is non-invasive and highly effective, it is not welltolerated by patients. Patient compliance for CPAP is often reported tobe between 40% and 60%.

Surgical treatment options for OSA are available too. However, they tendto be highly invasive (result in structural changes), irreversible, andhave poor and/or inconsistent efficacy. Even the more effective surgicalprocedures are undesirable because they usually require multipleinvasive and irreversible operations, they may alter a patient'sappearance (e.g., maxillo-mandibulary advancement), and/or they may besocially stigmatic (e.g., tracheostomy).

U.S. Pat. No. 4,830,008 to Meer proposes hypoglossal nerve stimulationas an alternative treatment for OSA. An example of an implantedhypoglossal nerve stimulator for OSA treatment is the Inspire™technology developed by Medtronic, Inc. (Fridley, Minn.). The Inspiredevice is not FDA approved and is not for commercial sale. The Inspiredevice includes an implanted neurostimulator, an implanted nerve cuffelectrode connected to the neurostimulator by a lead, and an implantedintra-thoracic pressure sensor for respiratory feedback, stimulustrigger, and/or timing of stimulus delivery. The Inspire device wasshown to be efficacious (approximately 75% response rate as defined by a50% or more reduction in RDI (Respiratory Disturbance Index) and a postRDI of .ltoreq.20) in an eight patient human clinical study, the resultsof which were published by Schwartz et al. and Eisele et al. However,both authors reported that only three of eight patients remained freefrom device malfunction, thus demonstrating the need for improvements.

Hypoglossal nerve stimulation has been proposed for the treatment ofobstructive sleep apnea. An example of an implantable hypoglossal nervestimulation system is described in U.S. Pat. No. 7,809,442 to Bolea etal. Published data suggest that response to hypoglossal nervestimulation varies across subjects. Before undergoing a surgicalprocedure to implant a hypoglossal nerve stimulation system, it would bedesirable to understand the likelihood of therapeutic success, and makeclinical judgments accordingly. It would also be desirable to consideradjunct therapies to hypoglossal nerve stimulation to improve outcomesthereof.

SUMMARY OF THE INVENTION

To address this and other unmet needs, the present disclosure provides,in exemplary non-limiting embodiments, devices, systems and methods fornerve stimulation for OSA therapy as described in the following detaileddescription.

In addition, to address this and other unmet needs, the presentdisclosure offers, in one example embodiment, a method for treatingobstructive sleep apnea by first performing an assessment of the patientthat involves observing the patient's upper airway during a tongueprotrusion maneuver. The assessment may, for example, be done usingendoscopy to observe the upper airway while the patient is awake in thesupine position. The tongue protrusion maneuver may, for example,involve the patient volitionally protruding the tongue to its maximalextent with the mouth open or the lips loosely touching the tongue. Thetongue protrusion maneuver mimics the effect of genioglossus activationby hypoglossal nerve stimulation (HGNS). Thus, an adequate increase inairway size during the tongue protrusion maneuver would be indicative oflikely therapeutic success with HGNS. If the assessment shows anadequate increase in airway size during the maneuver, a HGNS device maybe implanted in the patient with a higher confidence in a successfuloutcome. The principles of the present disclosure may be applied toother therapeutic interventions for OSA involving the upper airway.

Furthermore, to address this and other unmet needs, the presentdisclosure provides, by way of example, not limitation, embodiments ofdevices and methods for treating OSA and snoring by modifying pharyngealtissue of the upper airway such as, e.g., the palatoglossus,palatopharyngeus, pharyngeoepiglottis, and/or lateral walls. The methodsdescribed herein may be performed as an adjunct therapy or as astand-alone procedure. For example, the methods disclosed herein may becombined with interventions targeting the tongue such as, e.g.,hypoglossal nerve stimulation, genioglossus-advancement surgery,implantable devices that advance the tongue, mandibular advancementsurgery, mandibular advancement oral appliances, etc.

Embodiments of the present disclosure improve the mechanical couplingbetween the tongue, the soft palate and the lateral walls and/or improvethe mechanical properties of the connective structures. This may beaccomplished, for example, by shortening or stiffening the palatoglossalarch, palatopharyngeal arch, pharyngoepiglottic fold, and/or lateralwalls while retaining the integrity and function of the structures.

BRIEF DESCRIPTION OF THE DRAWINGS

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary. Together with the following detaileddescription, the drawings illustrate exemplary embodiments and serve toexplain certain principles. In the drawings:

FIG. 1 is a schematic diagram showing a fully implanted neurostimulatorsystem with associated physician programmer and patient controller fortreating obstructive sleep apnea;

FIG. 2 is a schematic diagram showing the implantable components of FIG.1 implanted in a patient;

FIG. 3 is a perspective view of the implantable components shown in FIG.1;

FIG. 4 is a detailed perspective view of the implantable neurostimulator(INS) shown in FIG. 3;

FIG. 5 is a detailed perspective view of the nerve cuff electrode andlead body shown in FIG. 3;

FIG. 5A is an illustration of exemplary movements a lead body may beconfigured to withstand;

FIG. 6 is a close-up detailed perspective view of the nerve cuffelectrode shown in FIG. 3;

FIG. 7 is a detailed perspective view of the internal components of thenerve cuff electrode shown in FIG. 6;

FIG. 8 shows side and end views of an electrode contact of the nervecuff electrode shown in FIG. 7;

FIGS. 9A and 9B are perspective views of the respiration sensing leadshown in FIG. 3;

FIG. 10 schematically illustrates surgical access and tunneling sitesfor implanting the system illustrated in FIG. 2;

FIGS. 11A and 11B schematically illustrate dissection to a hypoglossalnerve;

FIGS. 12 and 12A-12D schematically illustrate various possible nervestimulation sites for activating muscles controlling the upper airway;

FIGS. 13A, 13B, 14A-14C, 15A-15C, 16A-16F, 17, 18, 19A, 19B, 20, 21A,21B, 22 and 22A-22D are schematic illustrations of various stimulationlead body and electrode designs for use in a neurostimulator system;

FIGS. 23A, 23B, 23C, 24A, 24B, and 24C schematically illustratealternative implant procedures and associated tools for the stimulationlead;

FIG. 25 schematically illustrates an alternative bifurcated lead bodydesign;

FIGS. 26A-26B schematically illustrate alternative fixation techniquesfor the stimulation lead and electrode cuff;

FIG. 26C schematically illustrates an alternative embodiment of astimulation lead having a fixation mechanism;

FIGS. 27A-27H schematically illustrate field steering embodiments;

FIGS. 27I-27Q schematically illustrate alternative embodiments of nervecuff electrodes with selective fiber stimulation mechanisms;

FIGS. 28, 29A-29C, 30, 31A, 31B, 31B′, 31C, 32A, 32B, 33A, and 33Bschematically illustrate alternative fixation techniques for therespiration sensing lead;

FIG. 34 schematically illustrates the distal portion of an exemplaryrespiration sensing lead.

FIGS. 35A-35E and 36 schematically illustrate alternative electrodearrangements on the respiration sensing lead;

FIGS. 37 and 37A-37D schematically illustrate various anatomicalpositions or bio-Z vectors for the electrodes on the respiration sensinglead;

FIG. 38A illustrates an exemplary method of sampling a plurality ofvector signals;

FIGS. 38B, 38C, 39, 39A-39D, and 40-46 schematically illustratealternative respiration signal processing techniques;

FIG. 47 schematically illustrates an alternative respiration detectiontechnique;

FIGS. 47A-47D illustrate an exemplary stimulation trigger algorithm;

FIGS. 48-50 schematically illustrate alternative stimulation triggeralgorithms;

FIG. 50A illustrates an exemplary waveform of a patient's respiratorycycle;

FIG. 50B illustrates an exemplary stimulation waveform;

FIGS. 51A-51M are schematic illustrations of various external (partiallyimplanted) neurostimulation systems for treating obstructive sleepapnea;

FIGS. 52A-52H are schematic illustrations of a specific embodiment of anexternal (partially implanted) neurostimulation system;

FIGS. 53-56 schematically illustrate alternative screening tools; and

FIGS. 57A-57C, 58A, and 58B schematically illustrate alternativeintra-operative tools.

FIG. 59 is a schematic illustration of a system according to anembodiment of the present embodiment, including internal (chronicallyimplanted) and external components;

FIG. 60 is a perspective view of a stimulation lead for use in thesystem shown in FIG. 59, including a detailed view of the distal end ofthe stimulation lead;

FIG. 61A is a detailed perspective view of the cuff of the stimulationlead shown in FIG. 60;

FIG. 61B is a lateral cross-sectional view of the cuff shown in FIGS. 60and 61A;

FIG. 62A is a perspective view of a respiration sensing lead for use inthe system shown in FIG. 59;

FIG. 62B is a detailed perspective view of the proximal electrode pairof the respiration sensing lead shown in FIG. 62A;

FIG. 62C is a perspective view of an alternative respiration sensinglead for use in the system shown in FIG. 59;

FIG. 63A shows front, side and top views of an implantableneurostimulator for use in the system shown in FIG. 59;

FIG. 63B is a schematic block diagram of electronic circuitry for use inthe implantable neurostimulator shown in FIG. 63A;

FIGS. 64A, 64B, 64C and 64D illustrate a bio-impedance signal, thecorresponding physiological events, and trigger algorithms for use inthe system shown in FIG. 59;

FIG. 65A is a schematic illustration of the programmer system for use inthe system shown in FIG. 59;

FIGS. 65B and 65C are schematic block diagrams of electronic circuitryfor use in the programmer system for shown in FIG. 65A;

FIG. 66A is a schematic illustration of the therapy controller for usein the system shown in FIG. 59;

FIG. 66B is a schematic block diagram of electronic circuitry for use inthe therapy controller shown in FIG. 66A;

FIG. 67 is a top view of a magnet for use in the system shown in FIG.59;

FIG. 68A is a schematic illustration of an interface of the system shownin FIG. 59 and polysomnographic equipment as may be used in a sleepstudy for therapy titration or therapy assessment, for example;

FIG. 68B is a schematic illustration of an alternative interface of thesystem shown in FIG. 59;

FIGS. 69A and 69D are anatomical illustrations showing the incisionsites and tunneling paths that may be used for implanting the internalcomponents shown in FIG. 59;

FIG. 69B is a perspective view of a disassembled tunneling tool for usein tunneling the leads of the system shown in FIG. 59;

FIG. 69C is a detailed perspective view of the assembled tunneling toolshown in FIG. 69B, but with the cap removed to expose the jaws forgrasping the lead carrier disposed on the proximal end of a lead;

FIGS. 69E and 69F illustrate an alternative tunneling tool for use intunneling the leads of the system shown in FIG. 59;

FIG. 70 is a schematic illustration of an external stimulator system andpolysomnographic equipment as may be used for direct muscle stimulationusing fine wire electrodes as a therapy efficacy screening method, forexample;

FIG. 71 is a schematic illustration of a bio-impedance monitoring systemusing surface electrodes and polysomnographic equipment as may be usedas a respiratory sensing screening method, for example;

FIGS. 72A and 72B are charts showing various stimulation output modes ofthe implantable neurostimulator shown in FIG. 59 as may be used fortherapy titration, for example;

FIGS. 73A, 73B, 73C, 74A, 74B, 75, 76A and 76B are charts illustratingvarious therapy titration methodologies.

FIG. 77 is a schematic illustration of a system according to anembodiment of the present embodiment, including internal (chronicallyimplanted) and external components;

FIG. 78A is a perspective view of a bifurcated respiration sensing leadwhich may be used in the system shown in FIG. 77;

FIG. 78A1 is a detailed perspective view of the proximal connectorassembly of the respiration sensing lead shown in FIG. 77;

FIG. 78A2 is a detailed perspective view of the bifurcation section ofthe respiration sensing lead shown in FIG. 77;

FIG. 78A3 is a detailed perspective view of the contra-lateral distalbody portion of the respiration sensing lead shown in FIG. 77;

FIG. 78A4 is a detailed perspective view of the ipsi-lateral distal bodyportion in the respiration sensing lead shown in FIG. 77;

FIG. 78B is a detailed perspective view of an alternative embodiment ofthe respiration sensing lead which may be used in the system shown inFIG. 77;

FIG. 78B1 is a detailed perspective view of the proximal connectorassembly of the respiration sensing lead shown in FIG. 78B;

FIG. 78B2 is a detailed perspective view of the distal body portion ofthe respiration sensing lead shown in FIG. 78B;

FIG. 78C illustrates the implanted system shown in FIG. 77 with therespiration lead shown in FIG. 78A;

FIG. 78D illustrates the implanted system shown in FIG. 77 with therespiration lead shown in FIG. 78B;

FIG. 78E illustrates an alternative embodiment of the respirationsensing lead which may be used in the system shown in FIG. 77;

FIG. 78F illustrates an alternative embodiment of the respirationsensing lead containing a loop-back region. This lead may be used in thesystem shown in FIG. 77

FIG. 78G illustrates an alternative embodiment of the respirationsensing lead which may be used in the system shown in FIG. 77;

FIG. 78H illustrates an alternative embodiment of the respirationsensing lead which may be used in the system shown in FIG. 77;

FIG. 79A shows front, side and top views of an implantableneurostimulator for use in the system shown in FIG. 77;

FIG. 79B is a schematic block diagram of electronic circuitry for use inthe implantable neurostimulator shown in FIG. 5A;

FIGS. 80A, 80B, and 80C illustrate a bio-impedance signal, thecorresponding physiological events, and stimulation delivery algorithmsfor use in the system shown in FIG. 77;

FIGS. 80D, 80E, 80F, 80G, and 80H illustrate various stimulation pulseconfigurations for the implantable neurostimulator shown in FIG. 77, asmay be used for therapy or sleep titration, for example;

FIG. 80I (traces 1-8) shows various stimulation modes for theimplantable neurostimulator shown in FIG. 77, as may be used for therapyor sleep titration, for example;

FIG. 80J shows a stimulation regimen called core hours for theimplantable neurostimulator shown in FIG. 77, as may be used as atherapy mode;

FIG. 81 is an anatomical illustration showing the incision sites andtunneling paths that may be used for implanting the internal componentsshown in FIG. 77;

FIG. 82A shows a flowchart of an idealized therapy process and thesub-processes that may be involved;

FIGS. 82B, 82C, and 82D show detailed flowcharts of idealized therapysub-processes shown in FIG. 12A;

FIG. 83 (traces 1-8) illustrate various stimulation output modes of theimplantable neurostimulator shown in FIG. 77;

FIG. 84 illustrates an example of the effect of stimulation on airflow;and

FIG. 85 illustrates a sleep wand, for wireless communication with theneurostimulator during sleep.

FIG. 86 is a schematic illustration of a hypoglossal nerve stimulationsystem;

FIGS. 87A and 87B are schematic illustrations showing simplifiedstructures of the upper airway in a lateral dissection with the palateand mandible shown in medial sagittal section;

FIG. 88A is a schematic illustration showing an endoscope inserted intothe airway

FIGS. 88B and 88C are views of the upper airway from the endoscope shownin FIG. 88A while the tongue is in a resting awake state (FIG. 88B) andduring a tongue protrusion maneuver (FIG. 88C);

FIG. 88D is a schematic illustration of a modified endoscope;

FIG. 89 is a schematic illustration showing the structures of the upperairway in a lateral dissection with the palate and mandible shown inmedial sagittal section;

FIG. 90 is a schematic illustration showing the structures of the upperairway from the oral cavity;

FIG. 91 is a schematic illustration showing isolated structures of theupper airway in a transverse section;

FIG. 92 is a schematic illustration showing structures of the upperairway in a posterior dissection of the interior pharynx;

FIG. 93 is a schematic illustration showing structures of the upperairway in a posterior dissection of the exterior pharynx;

FIG. 94 is a schematic illustration showing the structures of the upperairway in a lateral dissection with the palate and mandible shown inmedial sagittal section;

FIGS. 95A-95F, 96A-96B, 97, and 98A-98B are schematic illustrations ofmethods for shortening pharyngeal tissue;

FIGS. 99A-99B are schematic illustrations of a tool for use in themethod shown in FIGS. 98A-98B;

FIGS. 100A-100B are schematic illustrations of a method for shorteningpharyngeal tissue using an implant device;

FIGS. 101A-101G are schematic illustrations of implant devices for usein the method shown in FIGS. 100A-100B;

FIGS. 102A-102B are schematic illustrations of a tool for use in themethod shown in FIGS. 100A-100B;

FIGS. 103A-103B are schematic illustrations of an alternative method forshortening pharyngeal tissue using an implant device;

FIGS. 104A-104D are schematic illustrations of implant devices for usein the method shown in FIGS. 103A-103B;

FIGS. 105A-105D are schematic illustrations of a tool for use in themethod shown in FIGS. 103A-103B;

FIGS. 106A-106D are schematic illustrations of an alternative tool foruse in the method shown in FIGS. 103A-103B;

FIGS. 107A-107F are schematic illustrations of alternative methods forshortening pharyngeal tissue using implant devices;

FIGS. 108A-108D are schematic illustrations of a palatal device; and

FIG. 109 is a schematic illustration of an oral device.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The following detailed description should be read with reference to thedrawings in which similar elements in different drawings are numberedthe same. The drawings, which are not necessarily to scale, depictillustrative embodiments and are not intended to limit the scope of theinvention.

Description of Fully Implanted Neurostimulator System

With reference to FIG. 1, a neurostimulator system 10 includingimplanted components 20, physician programmer 30 and patient controller40 is shown schematically. The implanted components of the system 10 maygenerally include an implanted neurostimulator (INS) 50 (a.k.a.,implanted pulse generator (IPG)), an implanted stimulation lead (orleads) 60, and an implanted respiration sensing lead (or leads) 70. TheINS 50 generally includes a header 52 for connection of the leads 60/70,and a hermetically sealed housing 54 for the associated electronics andlong-life or rechargeable battery (not visible). The stimulation lead 60generally includes a lead body 62 with a proximal connector and a distalnerve electrode cuff 64. The respiration sensing lead 70 generallyincludes a lead body 72 with a proximal connector and one or moresensors 74 disposed on or along a distal portion thereof. Suitabledesigns of the INS 50, stimulation lead 60 and respiration sensing lead70 are described in more detail hereinafter.

As shown in FIG. 2, and by way of example, not limitation, the implantedcomponents 20 (shown faded) of the neurostimulator system 10 areimplanted in a patient P with the INS 50 disposed in a subcutaneouspocket, the stimulation lead body 62 disposed in a subcutaneous tunnel,the nerve cuff electrode 64 disposed on a nerve (e.g., hypoglossal nerve(HGN)) innervating a muscle (e.g., genioglossus muscle, not shown)controlling the upper airway, the respiration sensing lead body 72disposed in a subcutaneous tunnel, and the respiration sensors 74disposed adjacent lung tissue and/or intercostal muscles outside thepleural space.

Generally, electrical stimulus is delivered by the INS 50 via thestimulation lead 60 to a nerve innervating a muscle controlling upperairway patency to mitigate obstruction thereof. To reduce nerve andmuscle fatigue, the stimulus may be delivered for only a portion of therespiratory cycle, such as during inspiration which corresponds tonegative pressure in the upper airway. Stimulation may be thus triggeredas a function of respiration as detected by respiration sensing lead 70in a closed-loop feedback system. By way of example, the stimulus may betriggered to turn on at the end of expiration (or at the beginning ofinspiration), and triggered to turn off at the beginning of expiration(or at the end of inspiration). Triggering the stimulus as a function ofexpiration improves capture of the entire inspiratory phase, including abrief pre-inspiratory phase of about 300 milliseconds, thus more closelymimicking normal activation of upper airway dilator muscles.Over-stimulation may cause nerve and/or muscle fatigue, but a 40% to 50%duty cycle may be safely tolerated, thus enabling limitedover-stimulation. As an alternative, stimulus may be deliveredindependent of actual respiration wherein the stimulus duty cycle is setfor an average inspiratory duration at a frequency approximately equalto an average respiratory cycle.

Stimulus may be delivered to one or more of a variety of nerve sites toactivate one muscle or muscle groups controlling patency of the upperairway. For example, stimulation of the genioglossus muscle via thehypoglossal nerve moves or otherwise stiffens the anterior portion ofthe upper airway, thereby decreasing the critical pressure at which theupper airway collapses during inspiration and reducing the likelihood ofan apnea or hypopnea event occurring during sleep. Because the systemsdescribed herein work at the level of the tongue, it may be desirable tocombine this therapy with a therapy (e.g., UPPP or palatal implant) thatwork at the level of the soft palate, thus increasing efficacy for abroader range of patients.

With reference back to FIG. 1, the physician programmer 30 may comprisea computer 32 configured to control and program the INS 50 via awireless link to a programming wand 34. The physician programmer 30 maybe resident in a sleep lab where the patient undergoes apolysomnographic (PSG) study during which the patient sleeps while theINS 50 is programmed to optimize therapy.

The patient controller 40 may comprise control circuitry and associateduser interface to allow the patient to control the system via a wirelesstelemetry link while at home, for example. The patient controller 40 mayinclude a power switch 42 to turn the system on and slowly ramp up whenthe patient goes to sleep at night, and turn it off when the patientwakes in the morning. A snooze switch 44 may be used to temporarily putthe INS 50 in standby mode during which electrical stimulus is pausedfor a preprogrammed period of time to allow the patient to temporarilywake, after which the INS 50 turns back on and ramps up to the desiredstimulus level. A display 46 may be provided to indicate the status ofthe INS 50 (e.g., on, off or standby), to indicate satisfactory wirelesstelemetry link to the INS 50, to indicate remaining battery life of theINS 50, to indicate normal operation of the INS 50, and/or to indicatethe need for patient action etc. Display 46 may be configured to be adash-board-like display, and may be any suitable display available tothose of ordinary skill in the art, such as, for example, an LED or LCDdisplay. Furthermore, information may be communicated to the patientcontroller 40 for display purposes by any suitable means known to thoseof ordinary skill in the art. For example, communication of informationmay be achieved through inductively coupled or radio frequencytelemetry. The patient controller 40 may also have programmability toadjust stimulus parameters (e.g., amplitude) within a pre-set rangedetermined by the physician in order to improve efficacy and/or toreduce sensory perception, for example. Optionally, the patientcontroller 40 may be configured to function as the programming wand 34of the physician programmer 30.

Furthermore, the patient controller 40 may be provided with one or moremechanisms for improving patient compliance. For example, patientcontroller 40 may be provided with a time-keeping mechanism having thecapabilities of a conventional alarm clock. In certain embodiments,controller 40 may be programmed by the user and/or the physician toalert the user when action, such as, for example, turning the system 10on or off, is required by the user. Controller 40 may be configured toalert the user by any suitable means known in the art. For example,controller 40 may emit an audible alarm at programmed time intervals. Inother embodiments, the patient controller 40 may be used to monitor apatient. For example, the patient controller 40 may be programmed toperiodically send reports of patient actions, patient compliance, systemstatus, etc., to a clinician or caregiver via a telephone or computernetwork.

With reference to FIG. 3, the implanted components 20 are shownschematically with more detail. The implanted components include INS 50,stimulation lead 60, and respiration sensing lead 70. The INS 50includes header 52 and housing 54. The stimulation lead 60 includes leadbody 62 and nerve cuff electrode 64. The respiration sensing lead 70includes lead body 72 and respiration sensors 74 (e.g., impedancesensing electrodes).

With reference to FIG. 4, the INS 50 is shown schematically in moredetail. The INS 50 includes header 52 that may be formed usingconventional molding or casting techniques and may comprise conventionalmaterials such as epoxy or polyurethane (e.g., Tecothane brandpolyurethane). The housing 54 may be formed using conventional stampingor forming techniques and may comprise conventional materials such astitanium or ceramic. The housing 54 may include one or more isolatedelectrodes, and/or if a conductive material is used for the housing 54,the housing 54 may comprise an electrode, which may be used forrespiratory sensing, for example. The housing 54 may be hermeticallysealed to the header 52 using conventional techniques. The header 52 mayinclude two or more receptacles for receiving the proximal connectors66/76 of the stimulation lead body 62 and respiration sensing lead body72. The connectors 66/76 may comprise a conventional design such as IS 1or other in-line designs. The header 52 may also include set screw sealsand blocks 56 for receiving set screws (not shown) that establishelectrical contact between the INS 50 and the conductors of the leads60/70 via connectors 66/76, and that establish mechanical fixationthereto. Some electrical contact may be achieved through spring type orcam-locked mechanisms. As shown, two set screw arrangements 56 are shownfor the stimulation lead 60 and four set screw arrangements 56 are shownfor the respiration sensing lead 70, but the number may be adjusted forthe number of conductors in each lead. A hole 58 may be provided in theheader 52 for securing the INS 50 to subcutaneous tissue using a sutureat the time of implantation.

The INS 50 may comprise a conventional implanted neurostimulator designused in neurostimulation applications, such as those available fromTexcel (US), CCC (Uruguay) and NeuroTECH (Belgium), but modified for thepresent clinical application in terms of stimulation signal parameters,respiratory signal processing, trigger algorithm, patient control,physician programming, etc. The INS may contain a microprocessor andmemory for storing and processing data and algorithms. Algorithms may bein the form of software and/or firmware, for example. One of severaldifferent embodiments of the neurostimulator may be implemented. Forexample, the neurostimulator may be an internal/implantedneurostimulator (INS) powered by a long-life primary battery orrechargeable battery, or an external neurostimulator (ENS) wirelesslylinked (e.g., inductive) to an implanted receiver unit connected to theleads. The INS (or the receiver, unit of the ENS) may be implanted andoptionally anchored in a number of different locations including asubcutaneous pocket in the pectoral region, the dorsal neck region, orcranial region behind the ear, for example.

The INS 50 may include any suitable circuitry and programming inaccordance with the principles of the present disclosure. In oneembodiment, INS 50 may include an activity sensor (not shown) forsensing the activity of a patient, including the amount of activity ofthe patient. The activity sensor may detect motion of a patient by anysuitable means available to those of ordinary skill in the art. Forexample, a patient's motion may be detected by, for example, using aninternal accelerometer and/or measuring the impedance of the patient'storso with, for example, the built-in respiration sensor discussedbelow, and/or measuring a tissue pressure on the surface of theimplanted INS 50.

The data corresponding to a patient's detected motion may be stored,evaluated, and utilized in any of a number of various ways. In oneembodiment, data corresponding to a patient's motion may be used todetermine whether a patient is sleeping or awake. For example, when apatient's activity level falls below a predetermined threshold, it maybe assumed that the patient is sleeping. Conversely, when the patient'sactivity level rises above the pre-determined threshold, it may beassumed that the patient is awake. The activity sensor therefore may beused to facilitate selectively applying treatment when the patient isdetected to be sleeping and/or inhibiting treatment when the patient isdetected to be awake. Alternatively, data corresponding to a patient'smotion may be evaluated over a long period of time, such as, forexample, the first few months of treatment, for indications ofimprovement in a patient's quality of life. It is contemplated thatincreases in a patient's average level of daily activity will correspondto successful treatment of OSA. This, in turn, may correspond toimprovements in the patient's quality of life.

Moreover, the INS 50 may include a long-life battery (not shown) whichrequires periodic replacement after years of service. Alternatively, theINS may include a rechargeable power source such as a rechargeablebattery or super capacitor that is used instead of the long-lifebattery. To facilitate recharging, the INS may include a receiver coilinductively linked to a transmitter coil that is connected to arecharging unit powered by a larger battery or line power. Because thepatient is stationary while sleeping, recharging may be scheduled tooccur sometime during sleep to eliminate the need to carry therecharging unit during daily activities. The transmitter coil and thereceiver coil may be arranged coaxially in parallel planes to maximizeenergy transfer efficiency, and may be held in proximity to each otherby a patch, garment, or other means as described with reference to theexternal neurostimulator embodiments. Other examples of neurostimulatordesigns will be described in more detail hereinafter.

With reference to FIG. 5, the stimulation lead 60 may comprise a varietyof different design embodiments and may be positioned at differentanatomical sites. For example, a nerve cuff electrode(s) 64 may beattached to a nerve(s) innervating musculature affecting patency of theupper airway. As an alternative or in addition, the nerve cuff electrode64 may be replaced with an intramuscular electrode and placed directlyin the musculature affecting patency of the upper airway. The nerveelectrode 64 may be attached to a specific branch of a nerve innervatingthe desired muscle(s), or may be attached to a proximal trunk of thenerve in which a specific fascicle innervating the desired muscle(s) istargeted by steering the stimulus with multiple electrodes. One or moreelectrodes may be used for attachment to one or more portions of nerveson one side (unilateral) of the body, or one or more electrodes may beused for attachment to one or more portions of nerves on both sides(bilateral) of the body. Variations in lead body 62 and electrode 64design as well as variations in the target stimulation site or siteswill be described in more detail hereinafter.

With continued reference to FIG. 5, the lead body 62 may be sigmoidshaped, for example, to reduce strain applied to the cuff electrode 64when the lead body 62 is subject to movement. The sigmoid shape, whichmay alternatively comprise a variety of other waveform shapes, may havea wavelength of approximately 1.0 to 1.5 cm, and an amplitude ofapproximately 0.75 to 1.5 cm, for example. The lead body 62 may comprisea tubular jacket with electrical conductors 68 extending therein. Thetubular jacket may comprise extruded silicone having an outside diameterof approximately 0.047 inches and an inside diameter of approximately0.023 inches, for example. The tubular jacket may optionally have acovering of co-extruded polyurethane, for example, to improvedurability. The conductors 68, shown in a transparent window in thejacket for purposes of illustration only, may comprise a bifilar coil ofinsulated (e.g., ETFE) braided stranded wire (BSW) of MP35NLT material.The number of conductors 68 is shown as two, but may be adjusteddepending on the desired number of independent electrodes used.

The various embodiments of stimulation leads, for example, stimulationlead 60, disclosed herein may be fabricated by any suitable means knownto those having ordinary skill in the art, and may be made from anysuitable material. For example, the discussed sigmoid shape of thetubular jacket of lead body 62 may be formed by first extruding siliconein a semi-cured or semi cross-linked state. Next, the semi cross-linkedextruded tubular jacket may be placed in a sigmoid mold and then allowedto become fully cross-linked. In particular, the semi cross-linkedextruded tubular jacket may be placed in an oven and heated to convertthe semi cross-linked silicone of the extruded tubular jacket to fullycross-linked silicone. Additionally, a lumen within the tubular jacketmay be created along a longitudinal axis of the tubular jacket by anysuitable means.

Furthermore, in accordance with the principles of the presentdisclosure, it is contemplated that one or more of the variousembodiments of stimulation leads disclosed herein may be implanted in ornear highly mobile portions of the body. For example, embodiments of thedisclosed stimulation leads may be implanted in the ventral neck, forexample, along a path between the clavicle and mandible of a patient.Additionally, although mastication, deglutition, and speech may resultin mechanical loading on an implanted stimulation lead, it has beenfound that gross movement of the head and neck may create highmechanical stresses in the conductors of the lead body, lead jacket, andthe junction between the conductor wires and the anchor points, such as,for example, the electrodes. Accordingly, it may be desirable toconfigure the various embodiments of stimulation leads to withstandcertain predetermined amounts of fatigue and/or stresses, which mayresult from mechanical loading on a lead body due to gross movements ofa patient's neck and head.

In particular, research has revealed that approximately 98% of thepopulation may experience a 38.5% elongation or less in the distancebetween the clavicle and angle of the mandible (e.g., adjacent acontemplated area of implantation for a stimulation lead in accordancewith the principles of this disclosure). It has also been found that theangular range of motion of the cervical spine between adjacent vertebraemay be approximately 12 degrees, thereby flexing the lead through thisangle with a bend radius assumed to be approximately 1.0 centimeter. SeeAugustus A. White III et al., Clinical Biomechanics of the Spine, pp.84, 356, and 373 (1978). Furthermore, the frequency of gross headmovement through the range of motion in the contemplated area ofimplantation has been estimated to be approximately 300,000 cycles peryear, or on the average approximately 50 times per waking hour.

Thus, it may be desirable to design a lead body that is capable ofwithstanding, among other things, the stresses imparted by theabove-noted head and neck movements for an extended amount of time, suchas, for example, ten years. In particular, in order to design a leadbody that may remain functional for the exemplary ten year implantedlife, it may be desirable to configure the lead bodies disclosed hereinto withstand at least the above noted elongation and ranges of motion.For example, since implanted lead bodies are likely to be elongated byat least 38.5%, it may be desirable to design lead bodies to withstandbeing elongated by a predetermined distance Y, such as, for example,approximately 40% (+/−2%) from an initial unstressed state, for aminimum of 3.0 million cycles without failure, as depicted in FIG. 5A.In addition, since it is likely that an implanted lead body mayexperience an angular range of motion of at least 12 degrees, with abend radius of approximately 1.0 centimeter, it may be desirable toconfigure the lead bodies to withstand being flexed around apredetermined radius X, such as, for example, 1.0 centimeter (+/−0.05centimeters), for a predetermined amount of rotation W, such as, forexample, from approximately 0 degrees to approximately 15 degrees (+/−3degrees), such that the 15 degree maximum deflection occurscoincidentally with the maximum elongation of the lead body.

With reference to FIG. 6, the nerve cuff electrode 64 may comprise acuff body 80 having a lateral (or superficial) side 82 and a medial (orcontralateral, or deep) side 84. The medial side 84 is narrower orshorter in length than the lateral side 82 to facilitate insertion ofthe medial side 84 around a nerve such that the medial side is on thedeep side of the nerve and the lateral side is on the superficial sideof the nerve. This configuration reduces the dissection of nervebranches and vascular supply required to get the cuff around a nerve.For the nerve cuff implant sites discussed herein, the medial side 84may have a length of less than 6 mm, and preferably in the range ofapproximately 3 to 5 mm, for example. The lateral side 82 may have alength of more than 6 mm, and preferably in the range of approximately 7to 8 mm, for example. The cuff body 80 may be compliant and may beavailable in different sizes with an inside diameter of approximately2.5 to 3.0 mm or 3.0 to 3.5 mm, for example. The cuff size may also beadjusted depending on the nominal diameter of the nerve at the site ofimplantation. The cuff body 80 may have a wall thickness ofapproximately 1.0 mm and may be formed of molded silicone, for example,and may be reinforced with imbedded fibers or fabrics. An integral towstrap 86 may be used to facilitate wrapping the cuff around a nerve byfirst inserting the strap 86 under and around the deep side of the nerveand subsequently pulling the strap to bring the medial side 84 inposition on the deep side of the nerve and the lateral side 82 on thesuperficial side of the nerve.

With continued reference to FIG. 6, the nerve cuff electrode 64 includeselectrode contacts 90A, 90B, and 90C imbedded in the body 80 of thecuff, with their inside surface facing exposed to establish electricalcontact with a nerve disposed therein. A transverse guarded tri-polarelectrode arrangement is shown by way of example, not limitation,wherein electrode contacts 90A and 90B comprise anodes transverselyguarding electrode contact 90C which comprises a cathode.

With this arrangement, the anode electrodes 90A and 90B are connected toa common conductor 68A imbedded in the body 80, and the cathodeelectrode 90C is connected to an independent conductor 68B extendingfrom the lateral side 82 to the medial side 84 and imbedded in the body80. By using the conductors 68 to make connections within the body 80 ofthe cuff 64, fatigue stresses are imposed on the conductors rather thanthe electrode contacts 90A, 90B and 90C.

With additional reference to FIGS. 7 and 8, the electrode contacts 90A,90B and 90C may thus be semi-circular shaped having an arc length ofless than 180 degrees, and preferably an arc length of approximately 120degrees, for example. Each electrode 90 may have two reverse bends(e.g., hooked or curled) portions 92 to provide mechanical fixation tothe body 80 when imbedded therein. Each electrode 90 may also have twocrimp tabs 94 defining grooves thereunder for crimping to the conductors68 or for providing a pass-through. As shown in FIG. 7, conductor 68Apasses through the grooves under the lower crimp tabs 94 of electrodes90B and 90A, loops 98 around through the grooves under the upper crimptabs 94 of electrodes 90A and 90B, is crimped 96 by the upper tabs 94 ofelectrodes 90A and 90B to provide mechanical and electrical connection,is looped again back between the crimp tabs 94 on the outside of theelectrode contact 90, and is resistance spot welded 95 to provideredundancy in mechanical and electrical connection. Also as shown inFIG. 7, conductor 68B passes through the groove under the lower crimptab 94 of electrode 90C, loops around through the groove under the uppercrimp tab 94 of electrode 90C, and is crimped by the upper tab 94 ofelectrode 90C to provide mechanical and electrical connection. Thisarrangement avoids off-axis tensile loading at the crimp sites 96 whichmay otherwise fail due to stress concentration, and the looped portion98 provides additional strain relief.

FIG. 8 provides example dimensions (inches) of an electrode contact 90for a 2.5 mm inside diameter cuff, wherein the electrode is formed of90/10 or 80/20 platinum iridium alloy formed by wire EDM, for example.As illustrated, and as exemplary and approximate dimensions, electrodecontact 90 may include a surface A having a full radius, a dimension Bof 0.079 inches from tangent to tangent, a dimension C of 0.020 inches(3.times.), a radius of curvature D of 0.049 R with a 16 micro-inch RMS,a dimension E of 0.008 inches (2.times.), a dimension F of 0.0065 inches(+/−0.001 inches) (2.times.), a dimension G of 0.006 inches (+0.002inches, −0.001 inches) (2.times.), a dimension H of 0.014 inches(2.times.), a dimension I of 0.010 inches (2.times.), a dimension J of0.010 inches (2.times.), and a dimension K of 0.006 inches (+/−0.001inches).

With reference to FIGS. 9A and 9B, a distal portion of the respirationsensing lead 70 and a distal detail of the sensing lead 70,respectively, are shown schematically. In the illustrated embodiment,the respiration sensing lead 70 and associated sensors 74 are implantedas shown in FIG. 2. However, the respiration sensor(s) may comprise avariety of different design embodiments, both implanted and external,and may be positioned at different anatomical sites. Generally, therespiratory sensor(s) may be internal/implanted or external, and may beconnected to the neurostimulator via a wired or wireless link. Therespiratory sensor(s) may detect respiration directly or a surrogatethereof. The respiratory sensor(s) may measure, for example, respiratoryairflow, respiratory effort (e.g., diaphragmatic or thoracic movement),intra-pleural pressure, lung impedance, respiratory drive, upper airwayEMG, changes in tissue impedance in and around the lung(s) including thelungs, diaphragm and/or liver, acoustic airflow or any of a number otherparameters indicative of respiration. Detailed examples of suitablerespiration sensing leads and sensors will be described in more detailhereinafter.

With continued reference to FIGS. 9A and 9B, the respiration sensinglead 70 includes a lead body 72 and a plurality of respiration sensors74A-74D comprising ring electrodes for sensing bio-impedance. The leadbody 72 of the respiration sensing lead 70 may include a jacket covercomprising an extruded silicone tube optionally including a polyurethanecover (80 A durometer), or may comprise an extruded polyurethane tube(55 D durometer). The ring electrodes 74A-74D may comprise 90/10 or80/20 platinum iridium alloy tubes having an outside diameter of 0.050inches and a length of 5 mm, and secured to the jacket cover by laserwelding and/or adhesive bonding, for example. The lead body 72 mayinclude a plurality of conductors 78 as seen in the transparent windowin the jacket cover, which is shown for purposes of illustration only.The conductors 78 may comprise insulated and coiled BSW or solid wire(optionally DFT silver core wire) disposed in the tubular jacket, withone conductor provided for each ring electrode 74A-74D requiringindependent control. Generally, the impedance electrodes 74A-74D maycomprise current emitting electrodes and voltage sensing electrodes fordetecting respiration by changes in bio-impedance. The number, spacing,anatomical location and function of the impedance electrodes will bedescribed in more detail hereinafter.

System 10 may also include a plurality of diagnostic mechanisms (e.g.,circuitry and/or programming) for monitoring and/or determining thefunctionality of certain components, such as, for example, stimulationlead 60. In particular, system 10 may include one or more switchingcircuits (not shown) that facilitate connection of therespiratory/trans-thoracic impedance sensing circuits of the presentdisclosure (discussed in greater detail below) to stimulation lead 60for measuring the impedance of lead 60. In some embodiments, theimpedance sensing circuit may be connected to each electrode pair. Inother embodiments, the impedance sensing circuit may be connectedbetween the case of the implanted INS 50 and each conductor 68 withinthe lead 60. While those having ordinary skill in the art will readilyrecognize that any suitable impedance sensing method may be utilized tomonitor and/or determine the functionality of lead 60, therespiratory/trans-thoracic impedance sensing circuit of the presentdisclosure may be preferred, since this circuit may be capable ofidentifying small changes in impedance rather than the large changesdetectable by standard methods.

As alluded to above, sensing the impedance of lead 60 may provide formonitoring and/or determining the functionality of lead 60.Specifically, sensing the impedance of lead 60 may facilitate diagnosingand distinguishing between differing types of failures of lead 60. Inparticular, research has revealed that changes in the impedance of lead60 may be indicative of certain types of failures, including, but notlimited to, corrosion, high contact resistance, breakage, and/orshorting. For example, a broken wire inside the lead could be identifiedby an excessively high lead impedance value. Corrosion of an electrodewith its resultant decrease in effective electrode surface area could beidentified by a smaller increase in impedance of that electrode.Similarly, an abnormally low value could correspond with a short betweenconductors in the lead, or an abrasion of the lead body that exposed aconductor to the tissue. Measuring from the case of the INS to eachelectrode allows independent identification of the integrity of eachwire/electrode in the lead. In addition, sensing the impedance of lead60 may facilitate periodic, automated adjustment of stimulation pulseamplitude so as to maintain constant current, energy, and/or chargedelivery using a simpler voltage mode delivery circuit. Such automatedadjustment may facilitate ensuring safety and effectiveness byconsistently delivering the prescribed current, energy, or charge in thepresence of tissue/electrode impedance variations. By consistentlycontrolling the delivery of only the minimally required energy necessaryfor stimulation of the nerve, the stimulation amplitude may beprogrammed closer to the actual stimulation threshold rather thanprogramming a wide margin to ensure continued effectiveness. Thisenhances safety and reduces power consumption. Moreover, sensing theimpedance of lead 60 may allow monitoring of certain system dynamics,such as, for example, doses actually delivered to a patient.

Description of Implant Procedure

With reference to FIG. 10, surgical access sites are schematically shownfor implanting the internal neurostimulator components 20 shown inFIG. 1. The internal neurostimulator components 20 may be surgicallyimplanted in a patient on the right or left side. The right side may bepreferred because it leaves the left side available for implantation ofa pacemaker, defibrillator, etc., which are traditionally implanted onthe left side. The right side may also be preferred because it lendsitself to a clean respiratory signal less susceptible to cardiacartifact and also offers placement of respiratory sensors across theinterface between the lung, diaphragm and liver for better detection ofimpedance changes during respiration.

With continued reference to FIG. 10, the INS (not shown) may beimplanted in a subcutaneous pocket 102 in the pectoral region, forexample. The stimulation lead (not shown) may be implanted in asubcutaneous tunnel 104 along (e.g., over or under) the platysma musclein the neck region. The respiration sensing lead (not shown) may beimplanted in a subcutaneous tunnel 106 extending adjacent the ribcage toan area adjacent lung tissue and/or intercostal muscles outside thepleural space. The nerve cuff electrode (not shown) may be attached to anerve by surgical dissection at a surgical access site 110 proximate thetargeted stimulation site. In the illustrated example, the target nerveis the right hypoglossal nerve and the surgical access site is in thesubmandibular region.

With reference to FIGS. 11A and 11B, a surgical dissection 110 to thehypoglossal nerve is shown schematically. A unilateral dissection isshown, but a bilateral approach for bilateral stimulation may also beemployed. Conventional surgical dissection techniques may be employed.The branch of the hypoglossal nerve (usually a medial or distal branch)leading to the genioglossus muscle may be identified by stimulating thehypoglossal nerve at different locations and observing the tongue forprotrusion. Because elongation and/or flexion may be mistaken forprotrusion, it may be desirable to observe the upper airway using aflexible fiber optic scope (e.g., nasopharyngoscope) inserted into thepatient's nose, through the nasal passages, past the nasopharynx andvelopharynx to view of the oropharynx and hypopharynx and visuallyconfirm an increase in airway caliber by anterior displacement(protrusion) of the tongue base when the nerve branch is stimulated.

The implant procedure may be performed with the patient under generalanesthesia in a hospital setting on an out-patient basis. Alternatively,local anesthesia (at the surgical access sites and along thesubcutaneous tunnels) may be used together with a sedative in a surgicalcenter or physician office setting. As a further alternative, a facialnerve block may be employed. After a post-surgical healing period ofabout several weeks, the patient may return for a polysomnographic (PSG)test or sleep study at a sleep center for programming the system andtitrating the therapy. A trialing period may be employed prior to fullimplantation wherein the hypoglossal nerve or the genioglossus muscle isstimulated with fine wire electrodes in a sleep study and the efficacyof delivering stimulus to the hypoglossal nerve or directly to thegenioglossus muscle is observed and measured by reduction in apneahypopnea index, for example.

Other nerve target sites are described elsewhere herein and may beaccessed by similar surgical access techniques. As an alternative tosurgical dissection, less invasive approaches such as percutaneous orlaparoscopic access techniques may be utilized, making use of associatedtools such as tubular sheaths, trocars, etc.

Description of Alternative Stimulation Target Sites

With reference to FIG. 12, various possible nerve and/or direct musclestimulation sites are shown for stimulating muscles controlling patencyof the upper airway. In addition to the upper airway which generallyincludes the pharyngeal space, other nerves and dilator muscles of thenasal passage and nasopharyngeal space may be selectively targeted forstimulation. A general description of the muscles and nerves suitablefor stimulation follows, of which the pharyngeal nerves and muscles areshown in detail in FIG. 12.

Airway dilator muscles and associated nerves suitable for activationinclude are described in the following text and associated drawings. Thedilator naris muscle functions to widen the anterior nasal aperture(i.e., flares nostrils) and is innervated by the buccal branch of thefacial nerve (cranial nerve VII). The tensor veli palatine musclefunctions to stiffen the soft palate and is innervated by the medial (orinternal) pterygoid branch of the mandibular nerve MN. The genioglossusmuscle is an extrinsic pharyngeal muscle connecting the base of thetongue to the chin and functions to protrude the tongue. Thegenioglossus muscle is typically innervated by a distal or medial branch(or braches) of the right and left hypoglossal nerve. The geniohyoidmuscle connects the hyoid bone to the chin and the sternohyoid muscleattaches the hyoid bone to the sternum. The geniohyoid muscle functionsto pull the hyoid bone anterosuperiorly, the sternohyoid musclefunctions to pull hyoid bone inferiorly, and collectively (i.e.,co-activation) they function to pull the hyoid bone anteriorly. Thegeniohyoid muscle is innervated by the hypoglossal nerve, and thesternohyoid muscle is innervated by the ansa cervicalis nerve.

By way of example, a nerve electrode may be attached to a specificbranch of the hypoglossal nerve innervating the genioglossus muscle(tongue protruder), or may be attached to a more proximal portion (e.g.,trunk) of the hypoglossal nerve in which a specific fascicle innervatingthe genioglossus muscle is targeted by steering the stimulus using anelectrode array. Activating the genioglossus muscle causes the tongue toprotrude thus increasing the size of anterior aspect of the upper airwayor otherwise resisting collapse during inspiration.

As an alternative to activation of any or a combination of the airwaydilator muscles, co-activation of airway dilator and airway restrictoror retruder muscles may be used to stiffen the airway and maintainpatency. By way of example, a nerve electrode may be attached tospecific branches of the hypoglossal nerve innervating the genioglossusmuscle (tongue protruder), in addition to the hyoglossus andstyloglossus muscles (tongue retruders), or may be attached to a moreproximal portion (e.g., trunk) of the hypoglossal nerve in whichspecific fascicles innervating the genioglossus, hyoglossus andstyloglossus muscles are targeted by steering the stimulus using anelectrode array. Activating the hyoglossus and styloglossus musclescauses the tongue to retract, and when co-activated with thegenioglossus, causes the tongue to stiffen thus supporting the anterioraspect of the upper airway and resisting collapse during inspiration.Because the tongue retruder muscles may overbear the tongue protrudermuscle under equal co-activation, unbalanced co-activation may bedesired. Thus, a greater stimulus (e.g., longer stimulation period,larger stimulation amplitude, higher stimulation frequency, etc.) or anearlier initiated stimulus may be delivered to the portion(s) of thehypoglossal nerve innervating the genioglossus muscle than to theportion(s) of the hypoglossal nerve innervating the hyoglossus andstyloglossus muscles.

With continued reference to FIG. 12, examples of suitable nervestimulation sites include B; A+C; A+C+D; B+D; C+D; and E. Sites B and Emay benefit from selective activation by field steering using anelectrode array. As mentioned before, nerve electrodes may be placed atthese target nerve(s) and/or intramuscular electrodes may be placeddirectly in the muscle(s) innervated by the target nerve(s).

Site A is a distal or medial branch of the hypoglossal nerve proximal ofa branch innervating the genioglossus muscle and distal of a branchinnervating the geniohyoid muscle. Site B is a more proximal portion ofthe hypoglossal nerve proximal of the branches innervating thegenioglossus muscle and the geniohyoid muscle, and distal of thebranches innervating the hyoglossus muscle and the styloglossus muscle.Site C is a medial branch of the hypoglossal nerve proximal of a branchinnervating the geniohyoid muscle and distal of branches innervating thehyoglossus muscle and the styloglossus muscle. Site D is a branch of theansa cervicalis nerve distal of the nerve root and innervating thesternohyoid. Site E is a very proximal portion (trunk) of thehypoglossal nerve proximal of the branches innervating the genioglossus,hyoglossus and styloglossus muscles.

Activating site B involves implanting an electrode on a hypoglossalnerve proximal of the branches innervating the genioglossus muscle andthe geniohyoid muscle, and distal of the branches innervating thehyoglossus muscle and the styloglossus muscle.

Co-activating sites A+C involves implanting a first electrode on ahypoglossal nerve proximal of a branch innervating the genioglossusmuscle and distal of a branch innervating the geniohyoid muscle, andimplanting a second electrode on the hypoglossal nerve proximal of abranch innervating the geniohyoid muscle and distal of branchesinnervating the hyoglossus muscle and the styloglossus muscle.

Co-activating sites A+C+D involves implanting a first electrode on ahypoglossal nerve proximal of a branch innervating the genioglossusmuscle and distal of a branch innervating the geniohyoid muscle;implanting a second electrode on the hypoglossal nerve proximal of abranch innervating the geniohyoid muscle and distal of branchesinnervating the hyoglossus muscle and the styloglossus muscle; andimplanting a third electrode on a branch of an ansa cervicalis nervedistal of the nerve root and innervating the sternohyoid.

Co-activating sites B+D involves implanting a first electrode on ahypoglossal nerve proximal of branches innervating the genioglossusmuscle and the geniohyoid muscle, and distal of branches innervating thehyoglossus muscle and the styloglossus muscle; and implanting a secondelectrode on a branch of an ansa cervicalis nerve distal of the nerveroot and innervating the sternohyoid.

Co-activating sites C+D involves implanting a first electrode on ahypoglossal nerve proximal of a branch innervating the geniohyoidmuscle, and distal of branches innervating the hyoglossus muscle and thestyloglossus muscle and implanting a second electrode on a branch of anansa cervicalis nerve distal of the nerve root and innervating thesternohyoid.

Activating site E involves implanting an electrode on a hypoglossalnerve proximal of the branches innervating the genioglossus, hyoglossusand styloglossus muscles; and selectively activating (e.g., by fieldsteering) the genioglossus muscle before or more than the hyoglossus andstyloglossus muscles.

With reference now to FIGS. 12A-12D, additional possible nervestimulation sites are shown for effecting muscles controlling patency ofthe upper airway. For example, the cranial root of the accessory nerveAN (cranial nerve XI) innervates the levator veli palatini muscle of thesoft palate, which elevates the soft palate. The cranial root of theaccessory nerve AN also innervates the palatoglossal muscle, whichfunctions to pull the soft palate inferiorly when the genioglossus isco-activated via the hypoglossal nerve (HGN). Moreover, because thecranial root of the accessory nerve AN also innervates various othermuscles including, but not limited to, the palatopharyngeus, specificfibers in the accessory nerve AN may be selectively stimulated with oneor more of the fiber selective stimulation means described in greaterdetail below, in order to only activate desired fibers of the nerve. Theglossopharyngeal nerve GN. (cranial nerve IX) innervates thestylopharyngeus, which functions to dilate the lateral walls of thepharynx. However, since the glossopharyngeal nerve GN is amulti-function nerve with both afferent and efferent fibers, one or moreof the fiber selective stimulation means described in greater detailbelow may be used to facilitate targeting the fibers that innervate onlythe stylopharyngeus. The cranial root of the accessory nerve AN and theglossopharyngeal nerve GN may be singularly activated, or these nervesmay be co-activated with other nerve sites, such as, for example, thehypoglossal nerve, for increased efficacy.

Another possible nerve stimulation site may include the superiorlaryngeal nerve SLN. The superior laryngeal nerve SLN descends posteriorand medial from the internal carotid artery and divides into theinternal laryngeal nerve ILN and external laryngeal nerve ELN. While theexternal laryngeal nerve ELN descends behind the sternohyoid with thesuperior thyroid artery, the internal laryngeal nerve ILN descends nearthe superior laryngeal artery. The internal laryngeal nerve ILN containssensory (afferent) fibers that are connected to receptors in the larynx.Some of these receptors include, but are not limited to,mechanoreceptors which detect pressure changes in a patient's upperairway associated with its collapse and institute a physiologicalresponse to re-open the patient's upper airway. Therefore, stimulationof specific afferent fibers inside the ILN nerve may result intriggering a reflex response that causes upper airway dilation byactivating several muscles groups.

As discussed below, the superior laryngeal nerve SLN, in addition tobeing a sensory nerve, is also a motor nerve. Therefore, it iscontemplated that one or more of the fiber selective stimulation meansdescribed in greater detail below may be utilized to facilitate onlystimulating the sensory or afferent fibers of the nerve.

Description of Alternative Nerve Electrodes

Any of the alternative nerve electrode designs described hereinafter maybe employed in the systems described herein, with modifications toposition, orientation, arrangement, integration, etc. made as dictatedby the particular embodiment employed. Examples of other nerve electrodedesigns are described in U.S. Pat. No. 5,531,778, to Maschino et al.,U.S. Pat. No. 4,979,511 to Terry, Jr., and U.S. Pat. No. 4,573,481 toBullara, the entire disclosures of which are incorporated herein byreference.

With reference to the following figures, various alternative electrodedesigns for use in the systems described above are schematicallyillustrated. In each of the embodiments, by way of example, notlimitation, the lead body and electrode cuff may comprise the same orsimilar materials formed in the same or similar manner as describedpreviously. For example, the lead body may comprise a polymeric jacketformed of silicone, polyurethane, or a co-extrusion thereof. The jacketmay contain insulated wire conductors made from BSW or solid wirecomprising MP35N, MP35N with Ag core, stainless steel or Tantalum, amongothers. The lead body may be sigmoid shaped to accommodate neck andmandibular movement. Also, a guarded cathode tri-polar electrodearrangement (e.g., anode-cathode-anode) may be used, with the electrodesmade of 90/10 or 80/20 PtIr alloy with silicone or polyurethane backing.

With specific reference to FIGS. 13A and 13B, a self-sizing andexpandable design is shown to accommodate nerve swelling and/orover-tightening. FIG. 13A shows a perspective view of a nerve electrodecuff 130 on a nerve such as a hypoglossal nerve, and FIG. 13B shows across-sectional view of the nerve cuff electrode 130 on the nerve. Inthis embodiment, the implantable nerve cuff electrode 130 comprises acompliant sheet wrap 132 configured to be wrapped about a nerve andsecured thereto by connecting opposite portions of the sheet by sutures138, for example. The sheet 132 includes a plurality of radially andlongitudinally distributed fenestrations 134 to allow expansion of thesheet 132 to accommodate nerve swelling and/or over tightening.Electrode contacts 136 comprising a coil, foil strip, conductiveelastomer or individual solid conductors may be carried by the sheet 132with an exposed inside surface to establish electrical contact with thenerve.

With specific reference to FIGS. 14A-14C, another self-sizing andexpandable design is shown to accommodate nerve swelling and/orover-tightening. FIG. 14A shows a perspective view of a nerve electrodecuff 140 on a nerve such as a hypoglossal nerve, and FIG. 14B shows across-sectional view of the nerve cuff electrode 140 on the nerve. Inthis embodiment, the implantable nerve cuff electrode 140 comprises acompliant sheet wrap 142 configured to be wrapped about a nerve andsecured thereto by connecting opposite portions of the sheet by sutures148A, or by a buckle 148B as shown in FIG. 14C, for example. Theopposite portions of the sheet 142 comprise one or more narrow strips144 integral with the sheet 142 to allow expansion and to accommodatenerve swelling and/or over tightening. Electrode contacts 146 comprisinga coil, foil strip, conductive elastomer or individual solid conductorsmay be carried by the sheet 142 with an exposed inside surface toestablish electrical contact with the nerve.

With specific reference to FIGS. 15A-15C, another self-sizing andexpandable design is shown to accommodate nerve swelling and/orover-tightening. FIG. 15A shows a perspective view of a nerve electrodecuff 150 on a nerve such as a hypoglossal nerve, and FIG. 15B shows across-sectional view of the nerve cuff electrode 150 on the nerve. Inthis embodiment, the implantable nerve cuff electrode 150 comprises acompliant sheet wrap 152 configured to be wrapped about a nerve andsecured thereto by connecting opposite portions of the sheet 152 bysutures 158, for example. The opposite portions of the sheet 152 areoffset from the nerve and a thickened portion of the sheet 152 fills theoffset space. The offset distance reduces the amount of compressiveforce that the electrode cuff can exert on the nerve. To further reducethe pressure on the nerve, the sheet 152 includes a plurality ofradially distributed slits 154 extending partly through the thickness ofthe sheet 152 to allow expansion and to accommodate nerve swellingand/or over tightening.

With specific reference to FIGS. 16A and 16B, another self-sizing andexpandable design is shown to accommodate nerve swelling and/orover-tightening. FIG. 16A shows a perspective view of a nerve electrodecuff 160 on a nerve such as a hypoglossal nerve, and FIG. 16B shows across-sectional view of the nerve cuff electrode 160 on the nerve. Inthis embodiment, the implantable nerve cuff electrode 160 comprises acompliant sheet wrap 162 configured to be wrapped about a nerve andsecured thereto by connecting opposite portions of the sheet 162 bysutures 168, for example. The sheet 162 includes a plurality of radiallydistributed and longitudinally extending convolutions 164 that maycomprise alternative thick 164A and thin 164B portions in the sheet 162and/or overlapping portions 164C of the sheet 162 to allow expansion andto accommodate nerve swelling and/or over tightening. Electrode contacts166 comprising a coil, foil strip, conductive elastomer or individualsolid conductors may be carried by the sheet 162 with an exposed insidesurface to establish electrical contact with the nerve. Nerve cuffelectrode 160 may accommodate one or two lead bodies 62A, 62B forconnection to the electrode contacts 166 on the same or opposite sidesof the nerve.

Turning now to FIGS. 16C-16D, additional self-sizing and expandabledesigns are shown to accommodate nerve swelling and/or over-tightening.With specific reference to FIG. 16C, there is depicted a nerve cuffelectrode 1600 having a cuff body with a relatively widesemi-cylindrical lateral side 1601 and a plurality of opposing arms 1602extending thereform for placement on the deep (contralateral) side ofthe nerve. Although the embodiment depicted in FIG. 16C includes twosuch opposing arms 1602, nerve cuff electrode 1600 may include anysuitable number of opposing arms 1602. Lateral side 1601 may include anarray of electrode contacts 1603. For example, in the depictedembodiment, lateral side may include three electrode contacts 1603. Thethree electrode contacts 1603 may include one cathode electrode contact1603 disposed between two anode electrode contacts 1603, as shown.

Arms 1602 may be secured around a nerve (not shown) by any suitablemeans. For example, it is contemplated that arms 1602 may be elastic innature, so as to gently grasp the nerve on its deep (contralateral)side. Alternatively, arms 1602 may be actively secured about a nerve by,for example, suturing an end portion of arms 1602 to, e.g., a portion oflateral side 1601. In embodiments where arms 1602 may be activelysecured about a nerve, arms 1602 may be provided with a safety mechanism(not shown) that permits nerve cuff electrode 1600 to become disengagedfrom a nerve it is secured about upon the application of a predeterminedamount of force. This predetermined force will be established at a levelthat is below that which can cause damage to the nerve.

As shown in FIG. 16D, opposing arms 1602 may be configured to expandand/or deform as necessary, in order to accommodate nerve swellingcaused by, for example, localized trauma inflicted upon the nerve duringcuff implantation. For example, each of opposing arms 1602 may have anunattached terminal end 1602 a. In order to facilitate expansion,opposing arms 1602 may be also made from any suitable material known tothose having ordinary skill in the art. For example, arms 1602 may bemade from an elastomer, such as, for example, silicone or polyurethane.Additionally, one or both of arms 1602 may be provided with one or morelimiting mechanisms (not shown) to limit the amount of expansion arms1602 may undergo as a result of, for example, nerve swelling. Suchlimiting mechanisms may include any suitable mechanism, including, butnot limited to, flanges, barbs, and/or sutures.

With reference to FIG. 16E, there is depicted another design of aself-sizing and expandable nerve cuff electrode 1610. For the purposesof this disclosure, nerve cuff electrode 1610 may be substantiallysimilar to nerve cuff electrode 1600 depicted in FIGS. 16C-16D. Nervecuff electrode 1610, however, may differ from nerve cuff electrode 1600in at least two significant ways. First, for example, lateral side 1611of nerve cuff electrode 1610 may carry two anode electrode contacts 1613and the medial side 1612 may carry one cathode electrode contact 1613 inan arrangement that may be referred to as transverse guarded tri-polar.Second, for example, nerve cuff electrode 1610 may include three arms1614-1616 extending from lateral side 1611. In the depicted embodiment,arms 1614 and 1616 may be configured to extend substantially in the samedirection from the same edge 1611 a of lateral side 1611, while arm 1615may be configured to extend in substantially the opposing direction froman opposing edge 1611 b of lateral side 1611. In the depictedembodiment, arm 1615 may be disposed between arms 1614 and 1616, and maybe configured to carry the cathode electrode contact 1613, as mentionedabove. However, any suitable arrangement of arms 1614-1616 and/orelectrode contacts 1613 may be utilized within the principles of thisdisclosure.

As shown in FIG. 16F, certain embodiments of nerve curve electrode 1600and/or nerve cuff electrode 1610 may include one or more elongated arms1617. Arms 1617 may include any suitable length, so as to allow arms1617 to wrap around a body portion of the cuff electrode one or moretimes in a spiral-like fashion, when the cuff electrode is mounted aboutan un-swollen nerve. However, arms 1617 may allow the cuff electrode toremain mounted on the nerve as it accommodates large amounts of nerveswelling by unraveling and/or unwrapping as the nerve swells. Forexample, each of the arms 1617 may overlap lateral side 1601 or 1611 toaccommodate larger amounts of nerve swelling without allowing the cuffto become detached from the nerve. The elongated arms 1617 may extendaround the body of the cuff electrode to form a spiral when the nerve isin a substantially un-swollen state, as shown.

With reference to FIG. 17, a modular nerve electrode cuff 170 is shownthat includes a semi-cylindrical body portion 172 with an array ofelectrode contacts 176 with separate insulative strips 174 for placementon the deep (contralateral side) of the nerve, which typically has morenerve branches and connecting blood vessels. In this embodiment,independent placement of the electrode body 172 on the superficial(lateral) side of the nerve and placement of the insulative strips 174on the deep (contralateral) side of the nerve minimizes dissection. Thestrips 174 may be connected to the electrode body 172 by sutures orbuckles as described previously. This embodiment is also self-sizing toaccommodate nerve swelling and/or over-tightening. With reference toFIG. 18, a nerve cuff electrode 180 is shown that has a cuff body with arelatively wide semi-cylindrical lateral side 182 and a relativelynarrow semi-cylindrical medial side 184 that may extend through a smallfenestration around the deep (contralateral) side of a nerve to securelyand gently grasp the nerve while minimizing dissection. In theillustrated example, the lateral side 182 carries two anode electrodecontacts 186 and the medial side 184 carries one cathode electrodecontact 186 in an arrangement that may be referred to as transverseguarded tri-polar. A tow strap 188 is provided for inserting the medialside 184 around the deep side of the nerve. The tow strap 188 may beintegrally formed with the medial side 184 of the cuff body, and mayinclude a reinforced tip 188A with a serrated or marked cut line 188B.

With reference to FIGS. 19A and 19B, a nerve cuff electrode 190 is shownthat has a cuff body with a relatively wide semi-cylindrical lateralside 192 and a relatively narrow semi-cylindrical medial side 194 thatmay extend through a small fenestration around the deep (contralateral)side of a nerve to securely and gently grasp the nerve while minimizingdissection. In the illustrated example, the lateral side 192 carries onecathode electrode contact 196C and two guarding anode electrode contacts196B and 196D, and the medial side 194 carries one anode electrodecontact 196A in an arrangement that may be referred to as transverse andlongitudinal guarded quad-polar. The provision of guarding electrodecontacts 196B and 196C reduces extrinsic stimulation due to the lack ofinsulative material on the medial side 194. The embodiments of FIGS. 18,19A and 19B illustrate two different electrode contact arrangements, butthe number and arrangement may be modified to suit the particularapplication.

With reference to FIG. 20, a nerve cuff electrode array 200 is shownthat utilizes a series of relatively narrow independent cuffs 200A, 200Band 200C with corresponding independent lead bodies 62. Providing aseries of relatively narrow independent cuffs 200A, 200B and 200Cminimizes the required dissection around the nerve for implantationthereof. Also, the series of independent cuffs 200A, 200B and 200Callows more selectivity in electrode placement to adjust for anatomicalvariation or multiple target stimulation sites, for example. Providingmultiple independent lead bodies 62 allows for more options in routingand placement of the individual lead bodies 62 (e.g., alternateplacement of lead body 62A) and also prevents tissue encapsulationaround the lead bodies 62 from collectively affecting encapsulation ofthe nerve cuffs 200. Each of the cuffs 200A, 200B and 200C may include acuff body 202 with one or more imbedded electrode contacts (not shown)and a tow strap 204 as described before. Also, each of the cuffs 200A,200B and 200C may include suture 208 or a buckle 206 to lock onto thetow strap 204 for connecting opposite ends of the body 202 around thenerve.

With reference to FIGS. 21A and 21B, a nerve cuff electrode 210 is shownwith multiple electrode contacts 216 radially spaced around the insidesurface of a compliant split cuff body 212 to establish multipleelectrical contact points around the circumference of the nerve. Each ofthe electrode contacts 216 may be connected to independent conductors inthe lead body 62 via axially extending wires 217. This arrangementallows for field steering as discussed herein. The compliant split cuffbody 212 together with axially extending wires 217 allows forself-sizing to accommodate nerve swelling and/or over-tightening. One ormore pairs of tabs 214 extending from opposite end portions of the cuffbody 212 may be connected by a suture (not shown) as described herein.As shown in FIG. 21B, the proximal and distal ends of the cuff body 212may have tapered thickness extensions 218 to provide strain relief andreduce mechanical irritation of the nerve due to contact with the edgeof the cuff.

With reference to FIG. 22, a nerve cuff electrode 220 is shown with aseparable lead 62 in what may be referred to as a modular design. Inthis embodiment, the nerve cuff electrode 220 includes a semi-circularflexible cuff body (or housing) 222 with a receptacle 224 configured toaccommodate a distal end of a lead body 62 therein. The receptacle 224may provide a releasable mechanical lock to the lead body 52 as by apress fit, mating detents, etc. The distal end of the lead body 62carries an array of ring electrodes 65, with windows 226 provided in thecuff body 222 configured to align with the ring electrodes 65 and permitexposure of the ring electrodes 65 to the nerve to establish electricalconnection therebetween. The cuff body 222 may be attached to the nerveor simply placed adjacent the nerve. Any of the cuff designs describedherein may be provided with a receptacle to accommodate a removable leadbody. This embodiment allows postoperative removal of the lead body 62without removal of the cuff 220, which may be beneficial in revisionoperations, for example.

Turning now to FIG. 22A, there is depicted another design for a nervecuff electrode 2000 where a substantially cylindrical distal portion 62′of lead body 62 carries an array of electrodes 2001. Electrodes 2001 mayinclude ring electrodes that extend completely around the circumferenceof lead body 62, or, alternatively, may include generally semi-circularelectrodes that extend partially around the circumference of lead body62. The electrode may be selectively insulated on any portion of itssurface to allow directional stimulation. Nerve cuff electrode 2000 mayfurther include a nerve securing mechanism for securing lead body 62 toa nerve, such as, for example, a hypoglossal nerve. The nerve securingmechanism may include, for example, a compliant sheet wrap 2002 that isattached on one end to a distal portion of lead body 62, and unattachedon the other opposing end. Compliant sheet wrap 2002 may be attached tolead body 62 by any suitable means.

As shown in FIG. 22B, compliant sheet wrap 2002 may be configured to bewrapped around a nerve and secured thereto by, for example, connectingopposite portions of the sheet wrap 2002 together. Sheet wrap 2002 maybe provided with one or more features to facilitate such connections.For example, it is contemplated that a portion 2002 b of sheet wrap 2002that is closest to lead body 62 may be provided with a projection 2002 cthat is configured for insertion into a corresponding opening 2002 eprovided on a portion 2002 d of sheet wrap 2002 that is opposite portion2002 b. Opening 2002 e may be configured to retain projection 2002 cdespite the forces exerted on sheet wrap 2002 during normal nerveswelling. However, opening 2002 e may be configured to releaseprojection 2002 c when forces greater than a predetermined threshold areexerted on sheet wrap 2002, so as to prevent injury to the nerve. Asshown in FIG. 22C, in some embodiments, opening 2002 e may be providedas a slot, which, in addition to securing projection 2002 c, may allowprojection 2002 c to slide within the opening 2002 e, thereby allowingexpansion of the sheet wrap 2002 to accommodate nerve swelling and/orover tightening of the sheet wrap 2002. Additionally, both portions 2002b and 2002 d may be provided with suitable openings to facilitate theinsertion of sutures (not shown) or other suitable fastening mechanisms.Sheet wrap 2002 may have any desired width. For example, sheet wrap 2002may have a substantially tapered width, in order to securely wrap thenerve while minimizing dissection.

Compliant sheet wrap 2002 may be provided with any of a number of meansthat allow sheet wrap 2002 to expand, in order to accommodate nerveswelling and/or over tightening. For example, in one embodiment, sheetwrap 2002 may be provided with a plurality of radially and/orlongitudinally distributed fenestrations (not shown). In otherembodiments, sheet wrap 2002 may be provided with a plurality ofundulations 2002 a, such as, for example, sigmoid undulations, which mayallow for expansion of sheet wrap 2002.

With reference now to FIG. 22D, there is depicted another design for anerve cuff electrode 2200 where a distal portion 62″ of lead body 62carries an array of electrodes 2201. For the purposes of thisdisclosure, nerve cuff electrode 2200 may include substantially the samefeatures as nerve cuff electrode 2000 depicted in FIGS. 22A-22C. Nervecuff electrode 2200, however, may differ from nerve cuff electrode 2000in that distal portion 62″ may be substantially flat or paddle-shaped.Furthermore, electrode contacts 2201, rather than being circular orsemi-circular in configuration, may be substantially, flat inconfiguration. In certain procedures, it is contemplated that thepaddle-shaped distal portion 62″, along with the substantially flatelectrode contacts 2201, may promote greater contact between electrodecontacts 2201 and the nerve they are mounted upon.

Description of Alternative Implant Procedure for the Stimulation Lead

With reference to FIGS. 23A-23C, an insertable paddle-shaped lead 230design is shown. The insertable lead 230 may have a paddle-shape(rectangular) cross-section with a tubular jacket 232 and one or moreconductors 234 extending therethrough to one or more distally placedelectrode contact(s) 236. The electrode contact(s) 236 may be imbeddedin a molded distal end of the jacket 232 such that the electrode contact236 has an exposed surface to face the nerve when implanted as shown inFIG. 23B. The space between the nerve and electrode is shown forpurposes of illustration only, as the electrodes may be placed in directcontact with the nerve. Soft tines 238 may be integrally formed at thedistal end of the tubular jacket 232 for purposes of mild fixation totissue when implanted. The insertable lead 230 is configured to beplaced adjacent to the nerve (thereby negating the need for a cuff) byinserting the lead 230 at the surgical access site 110 and following thenerve distally until the electrode contacts 236 are placed adjacent thetarget stimulation site. The insertable lead 232 may be used alone or inconjunction with another lead as shown in FIGS. 23B and 23C. In theillustrated example, a first lead 230A is inserted along a superficialside of the nerve and a second lead 230B is inserted along a deep sideof the nerve.

A method of implanting lead 230 may generally comprise accessing aproximal extent of the nerve by minimal surgical dissection andretraction of the mylohyoid muscle as shown in FIG. 23C. Special toolsmay alternatively be employed for percutaneous or laparoscopic access asshown and described with reference to FIGS. 24A-24C. Subsequently, twopaddle-shaped leads 230 with distal electrode contacts 236 may beinserted into the surgical access site and advanced beyond the accesssite along a distal aspect of the nerve to the desired stimulation siteon either side of the nerve. These techniques minimize trauma andfacilitate rapid recovery.

A less invasive method of implanting a paddle-shaped lead 230 is shownin FIGS. 24A-24C. In this embodiment, a rectangular tubular trocar 240with a sharpened curved tip is placed through a percutaneous access site111 until a distal end thereof is adjacent the superficial side of thenerve. A paddle-shaped lead 230 is inserted through the lumen of thetrocar 240 and advanced distally beyond the distal end of the trocar 240along the nerve, until the electrode contacts 236 are positioned at thetarget stimulation site. As shown in FIG. 24B, which is a view takenalong line A-A in FIG. 24A, the insertable lead 230 includes multipleelectrode contacts 236 in an anode-cathode-anode arrangement, forexample, on one side thereof to face the nerve when implanted. In thisembodiment, tines are omitted to facilitate smooth passage of the lead230 through the trocar. To establish fixation around the nerve and toprovide electrical insulation, a backer strap 242 of insulative materialmay be placed around the deep side of the nerve. To facilitatepercutaneous insertion of the backer 242, a curved tip needle 244 may beinserted through a percutaneous access site until the tip is adjacentthe nerve near the target stimulation site. A guide wire 246 with aJ-shaped tip may then be inserted through the needle 244 and around thenerve. The backer 242 may then be towed around using the guide wire 246as a leader, and secured in place by a buckle (not shown), for example.

With reference to FIG. 25, a bifurcated lead 250 is shown to facilitateseparate attachment of electrode cuffs 64 to different branches of thesame nerve or different nerves for purposes described previously. Any ofthe nerve cuff electrode or intramuscular electrode designs describedherein may be used with the bifurcated lead 250 as shown. In theillustrated example, a first lead furcation 252 and a second leadfurcation 254 are shown merging into a common lead body 62. Eachfurcation 252 and 254 may be the same or similar construction as thelead body 62, with modification in the number of conductors. More thantwo electrode cuffs 64 may be utilized with corresponding number of leadfurcations.

Description of Stimulation Lead Anchoring Alternatives

With reference to FIGS. 26A and 26B, an elastic tether 264 with alimited length is utilized to prevent high levels of traction on theelectrode cuff 64 around the hypoglossal nerve (or other nerve in thearea) resulting from gross head movement. In other words, tether 264relieves stress applied to the electrode cuff 64 by the lead body 62.FIGS. 26A and 26B are detailed views of the area around the dissectionto the hypoglossal nerve, showing alternative embodiments of attachmentof the tether 264. The proximal end of the tether 264 may be attached tothe lead body 62 as shown in FIG. 26A or attached to the electrode cuff64 as shown in FIG. 26B. The distal end of the tether 264 may beattached to the fibrous loop carrying the digastrics tendon as shown inFIG. 26A or attached to adjacent musculature as shown in FIG. 26B.

By way of example, not limitation, and as shown in FIG. 26A, a tubularcollar 262 is disposed on the lead body 62 to provide connection of thetether 264 to the lead body 62 such that the lead body 62 is effectivelyattached via suture 266 and tether 264 to the fibrous loop surroundingthe digastrics tendon. The tether 264 allows movement of the attachmentpoint to the lead body 62 (i.e., at collar 262) until the tether 264 isstraight. At this point, any significant tensile load in the caudaldirection will be borne on the fibrous loop and not on the electrodecuff 64 or nerve. This is especially advantageous during healing beforea fibrous sheath has formed around the lead body 62 and electrode cuff64, thus ensuring that the cuff 64 will not be pulled off of the nerve.It should be noted that the length of the tether 262 may be less thanthe length of the lead body 62 between the attachment point (i.e., atcollar 262) and the cuff 64 when the tensile load builds significantlydue to elongation of this section of lead body 62.

The tether 264 may be formed from a sigmoid length of braided permanentsuture coated with an elastomer (such as silicone or polyurethane) tomaintain the sigmoid shape when in the unloaded state. The tether 264may also be made from a monofilament suture thermoformed or molded intoa sigmoid shape. The distal end of the tether 264 may be attached to thefibrous loop using a suture 266 or staple or other secure means. Notethat the tether 264 may be made from a biodegradable suture that willremain in place only during healing.

Also by way of example, not limitation, an alternative is shown in FIG.26B wherein the tether 264 is attached to the electrode cuff 64. Thedistal end of the tether 264 may be attached to the adjacent musculatureby suture 266 such the musculature innervated by branches of thehypoglossal nerve or other musculature in the area where the electrodecuff 64 is attached to the nerve. The tether 264 ensures that theelectrode cuff 64 and the hypoglossal nerve are free to move relative tothe adjacent musculature (e.g., hyoglossal). As significant tensile loadis applied to the lead body 62 due to gross head movement, the tether264 will straighten, transmitting load to the muscle rather then to thenerve or electrode cuff 64.

As alluded to above, stimulation lead 60 may comprise a number ofdiffering design embodiments. One such embodiment has been discussedabove with respect to FIG. 5. Another such embodiment is depicted inFIG. 26C, which illustrates a stimulation lead 2600. Stimulation lead2600 may be substantially similar to and/or may include one or more ofthe features described in connection with stimulation lead 60. As shownin FIG. 26C, stimulation lead 2600 may include a lead body 2662 having afirst, proximal lead body portion 2663. First lead body portion 2663 maybe substantially similar to lead body 62. For example, first lead bodyportion 2663 may include a similar flexibility as lead body 62. Leadbody 2662 may further include a second, distal lead body portion 2664leading to the distal end of lead body 2662 at the nerve cuff electrode.Second lead body portion 2664 may include a material property that isdifferent than lead body portion 2663, such as, for example, a greaterflexibility, in order to accommodate stresses imparted upon lead body2662 by a nerve cuff electrode and movement of the patient's head, neck,and other neighboring body portions. The highly flexible distal portion2664 reduces the stress (torque and tension) imparted by lead body 2662on the electrode cuff, thereby reducing the likelihood that the cuffwill be detached from the nerve or damage the nerve.

Lead body portion 2664 may be made more flexible than lead body portion2663 by any of a variety of ways. For example, lead body portion 2664may be made from a material having differing flexibility. Alternatively,the diameters of the braided stranded wires (BSW) and/or wire insulationthat make up the lead body portion 2664 may be reduced when possible.

With continuing reference to FIG. 26C, stimulation lead 2600 may furtherinclude an anchor 2665 operably connected to lead body 2662. Althoughanchor 2665 in the illustrated embodiment is depicted as being disposedin between lead body portions 2663 and 2664, anchor 2665 may be disposedat any suitable location along the length of lead body 2662.Furthermore, anchor 2665 may be fixedly or movably connected to leadbody 2662.

Anchor 2665 may include any suitable configuration known in the art. Forexample, anchor 2665 may include a substantially flat body portion 2666.Body portion 2666 may be configured to be secured to tissue, such as,for example, tissue proximate a treatment site, by any suitable meansavailable in the art. For example, body portion 2666 may be providedwith openings 2667 to facilitate, for example, suturing anchor 2665 tonearby tissue. Anchor 2665 can thereby isolate stress (tension) to oneportion of lead body 2662, and particularly portion 2663, caused bygross head and neck movement.

Description of Field Steering Alternatives

With reference to FIGS. 27A-27G, a field steering nerve cuff electrode64 is shown schematically. As seen in FIG. 27A, the nerve cuff electrode64 may include four electrode contacts 90A-90D to enable field steering,and various arrangements of the electrode contacts 90A-90D are shown inFIGS. 27B-27G. Each of FIGS. 27B-27G includes a top view of the cuff 64to schematically illustrate the electrical field (activating function)and an end view of the cuff 64 to schematically illustrate the area ofthe nerve effectively stimulated. With this approach, electrical fieldsteering may be used to stimulate a select area or fascicle(s) within anerve or nerve bundle to activate select muscle groups as describedherein.

With specific reference to FIG. 27A, the nerve cuff electrode 64 maycomprise a cuff body having a lateral (or superficial) side 82 and amedial (or contralateral, or deep) side 84. The medial side 84 isnarrower or shorter in length than the lateral side 82 to facilitateinsertion of the medial side 84 around a nerve such that the medial sideis on the deep side of the nerve and the lateral side is on thesuperficial side of the nerve. An integral tow strap 86 may be used tofacilitate wrapping the cuff around a nerve. The nerve cuff electrode 64includes electrode contacts 90A, 90B, 90C and 90D imbedded in the bodyof the cuff, with their inside surface facing exposed to establishelectrical contact with a nerve disposed therein. Electrode contacts 90Aand 90B are longitudinally and radially spaced from each other.Electrode contacts 90C and 90D are radially spaced from each other andpositioned longitudinally between electrode contacts 90A and 90B. Eachof the four electrode contacts may be operated independently via fourseparate conductors (four filar) in the lead body 62.

With specific reference to FIGS. 27B-27G, each includes a top view (leftside) to schematically illustrate the electrical field or activatingfunction (labeled E), and an end view (right side) to schematicallyillustrate the area of the nerve effectively stimulated (labeled S) andthe area of the nerve effectively not stimulated (labeled NS).Electrodes 90A-90D are labeled A-D for sake of simplicity only. Thepolarity of the electrodes is also indicated, with each of the cathodesdesignated with a negative sign (−) and each of the anodes designatedwith a positive sign (+).

With reference to FIG. 27B, a tripolar transverse guarded cathodearrangement is shown with electrodes C and D comprising cathodes andelectrodes A and B comprising anodes, thus stimulating the entirecross-section of the nerve.

With reference to FIG. 27C, a bipolar diagonal arrangement is shown withelectrode C comprising a cathode and electrode A comprising an anode,wherein the fascicles that are stimulated may comprise superiorfascicles of the hypoglossal nerve, and the fascicles that are notstimulated may comprise inferior fascicles of the hypoglossal nerve(e.g., fascicles that innervate the intrinsic muscles of the tongue.

With reference to FIG. 27D, another bipolar diagonal arrangement isshown with electrode D comprising a cathode and electrode B comprisingan anode, wherein the fascicles that are stimulated may compriseinferior fascicles of the hypoglossal nerve.

With reference to FIG. 27E, a bipolar axial arrangement is shown withelectrode A comprising a cathode and electrode B comprising an anode,wherein the fascicles that are stimulated may comprise lateral fasciclesof the hypoglossal nerve.

With reference to FIG. 27F, a bipolar transverse arrangement is shownwith electrode C comprising a cathode and electrode D comprising ananode, wherein the fascicles that are stimulated may comprise medialfascicles of the hypoglossal nerve.

With reference to FIG. 27G, a modified tripolar transverse guardedcathode arrangement is shown with electrode C comprising a cathode andelectrodes A and B comprising anodes, thus stimulating the entirecross-section of the nerve with the exception of the inferior medialfascicles.

Nerves like the hypoglossal nerve or superior laryngeal nerve typicallyinclude a plurality of fibers having relatively larger diameters and aplurality of fibers having relatively smaller diameters. In the case ofsingle function nerves, such as, for example, the hypoglossal nerve HGN,all of the nerve fibers may either be sensory or motor in function.However, in the case of multi-function nerves, such as, for example, thesuperior laryngeal nerve SLN, the fibers having relatively largerdiameters are typically motor (efferent) fibers, and the fibers havingrelatively smaller diameters are typically sensory (afferent) fibers.Accordingly, there may be a need to selectively stimulate the differingdiameter fibers in a nerve.

Turning now to FIG. 27H, there is depicted an embodiment of auni-directional stimulation electrode 2700 having a distal end 2700 aand a proximal end 2700 b. Electrode 2700 may include a substantiallycylindrical nerve cuff 2701 in accordance with the principles of thepresent disclosure. As illustrated, nerve cuff 2701 may include an outersurface 2701 a and an inner surface 2701 b. Electrode 2700 may furtherinclude a plurality of electrode contacts 2702-2704. Electrode contacts2702-2704 may be used as any suitable electrode contact known to thoseof ordinary skill in the art. For example, electrode contact 2702 may beused as an anode, electrode contact 2703 may be used as a cathode, andelectrode contact 2704 may be used as a second anode. Electrode contacts2702-2704 may also include any suitable shape and/or configuration knownin the art. For example, electrode contacts 2702-2704 may include asubstantially semi-circular configuration.

Electrode contacts 2702-2704 may be disposed on nerve cuff 2701 in anysuitable configuration to achieve the desired effect. For example,electrode contacts 2702-2704 may be disposed on inner surface 2701 b. Asdepicted in FIG. 27H, cathode electrode contact 2703 may be disposedapproximately equidistant from distal end 2700 a and proximal end 2700b, and anode electrode contacts 2702 may be differentially spaced aroundcathode electrode contact 2703, so as to control the direction ofstimulation of electrode 2700. For example, anode electrode contact 2702may be spaced from cathode electrode contact 2703 by any suitabledistance .chi., while second anode electrode contact 2704 may be spacedfrom cathode electrode contact 2703 by a distance that is approximatelytwo or three times greater than distance .chi. In this exemplaryconfiguration, the direction of stimulation may be in the direction ofarrow 2705.

In use, electrode 2700 may be implanted upon a nerve in accordance withthe principles of this disclosure. Electrode 2700 may be oriented on thenerve it is implanted on in any suitable manner, such as, for example,according to the direction of intended stimulation. Thus, incircumstances where it may be desired to stimulate efferent (motor)fibers of a nerve, such as, for example, the superior laryngeal nerveSLN, while avoiding stimulation to afferent (sensory) fibers of thenerve, the electrode 2700 may be oriented on the nerve in a manner suchthat anode electrode contact 2702 is located distally of cathodeelectrode contact 2703, with distal and proximal designations based onthe relative location of the electrode contact on the nerve.Alternatively, in circumstances where it may be desired to stimulateafferent fibers of a nerve while avoiding stimulation of efferent fibersof the nerve, the electrode 2700 may be oriented on the nerve in amanner such that anode electrode contact 2702 is located proximally ofcathode electrode contact 2703.

With reference now to FIG. 27I, there is depicted an embodiment of astimulation electrode 2750 for, among other things, selectivelystimulating differing diameter fibers of a nerve, such as, for example,the hypoglossal nerve or superior laryngeal nerve. Electrode 2750 mayinclude a body 2751, and may include any suitable configuration inaccordance with the principles of the present disclosure. Additionally,electrode 2750 may include an array 2752 of suitable electrode contactsknown to those skilled in the art. Although the depicted embodiment ofelectrode 2750 includes five electrode contacts 2753 a-2753 e, array2752 may include a greater or lesser number of electrode contacts.Electrode contacts 2753 a-2753 e may be disposed on body 2751 in anysuitable configuration to produce the desired effect. For example, asdepicted in FIG. 27I, electrode contacts 2753 a-2753 e may be disposedserially, with approximately a one (1) millimeter spacing in betweeneach electrode contact 2753 a-2753 e. Electrode contacts 2753 a-2753 emay be configured to function as either anode electrode contacts orcathode electrode contacts, as desired.

Electrode contacts 2753 may be connected to an implanted neurostimulator(INS), such as, for example, INS 50, in accordance with the presentdisclosure. The INS may be programmed to select any of electrodecontacts 2753 a-2753 e for nerve stimulation. For example, incircumstances where it may be desired to stimulate the smaller diameterfibers of a nerve, it is contemplated that all electrode contacts 2753a-2753 e may be selected for nerve stimulation, since closely spacedelectrode contacts typically affect smaller diameter fibers (e.g.,afferent or sensory fibers). In these circumstances, electrode contacts2753 a, 2753 c, and 2753 e may function as anode electrode contacts andelectrode contacts 2753 b and 2753 d may function as cathode electrodecontacts. In circumstances where it may be desired to stimulate thelarger diameter fibers of a nerve, it is contemplated that onlyelectrode contacts 2753 a, 2753 c, and 2753 e may be selected for nervestimulation, since loosely spaced electrode contacts typically affectlarger diameter fibers (e.g., efferent or motor fibers). In thesecircumstances, electrode contacts 2753 a and 2753 e may function asanode electrode contacts, and 2753 c may function as a cathode electrodecontact.

Alternatively, electrode 2750 may be utilized to reduce muscle fatiguewhen implanted on single function nerves, such as, for example, thehypoglossal nerve. In such circumstances, muscle fatigue may be reducedby alternatively switching between using loosely spaced electrodecontacts 2753 a, 2753 c, and 2753 e, to stimulate large diameter fibers,and closely spaced electrode contacts 2753 a-2753 e, to stimulate smalldiameter fibers.

Turning to FIGS. 27J-27K, in accordance with the present disclosure,there is depicted another embodiment of a nerve cuff electrode 2760 forfacilitating reduction in muscle fatigue. Nerve cuff electrode 2760 mayinclude a body 2761 having a plurality of electrode contacts 2762, 2763,and 2764. Electrode contacts 2762-2764 may include any suitableelectrode contacts in accordance with the present disclosure. Althoughthe depicted embodiment of nerve cuff electrode 2760 includes threeelectrode contacts 2762-2764, nerve cuff electrode 2760 may include agreater or lesser number of electrode contacts. Furthermore, electrodecontacts may be disposed on body 2761 in any suitable configuration toachieve the desired effect, such as, for example, serially, as depicted.In the depicted embodiment, electrode contacts 2762 and 2764 mayfunction as anode electrode contacts, while electrode contact 2763 mayfunction as a cathode electrode contact. Electrode contact 2763 mayinclude two distinct, substantially triangularly shaped portions 2763 aand 2763 b. However, portions 2763 a and 2763 b may include any suitableshape. In addition, portions 2763 a and 2763 b may be configured to beof differing conductive properties, so that, for the same stimulationpulse (e.g., a slow rising, small amplitude pulse having a relativelylong duration of approximately 0.2 to 0.35 milliseconds) applied to eachof the portions 2763 a and 2763 b, the resultant charge densities at thesurface of each of the portions 2763 a and 2763 b may be different. Forexample, portions 2763 a and 2763 b may be made of electricallydiffering materials. For discussion purposes only, it is assumed thatportion 2763 a is configured to deliver a charge density lower than thatof portion 2763 b. However, portion 2763 a may be configured to delivera charge density that is higher than the charge density of portion 2763b.

Since the small diameter fibers of a nerve are typically stimulated bylow charge densities and large diameter fibers of the nerve aretypically stimulated by high charge densities, portions 2763 a and 2763b may be sequentially utilized to alternate between stimulating thesmall and large diameter fibers of a nerve. In other words, in use, astimulation pulse may be first delivered to portion 2763 a to stimulatethe small diameter fibers of a nerve. A subsequent stimulation pulse maybe then delivered to portion 2763 b to stimulate the large diameterfibers of a nerve. It is contemplated that alternating betweenstimulating the small and large diameter fibers of a nerve mayfacilitate reducing muscle fatigue while also ensuring sufficient musclemass is stimulated to maintain the necessary contraction and forcegeneration to successfully treat OSA.

Turning now to FIG. 27L, there is illustrated yet another embodiment ofa nerve cuff electrode 2780 for facilitating reduction in musclefatigue. For the purposes of this disclosure, nerve cuff electrode 2780may be substantially similar to nerve cuff electrode 2760. Nerve cuffelectrode 2780, however, may differ from nerve cuff electrode 2760 in atleast one significant way. For example, rather than having twosubstantially triangular portions, cathode electrode contact 2783 maycomprise two substantially different portions 2783 a and 2783 b.Portions 2783 a and 2783 b may be spaced apart from one another and mayinclude differing surface areas. For example, as illustrated, portion2783 a may include a smaller surface area than portion 2783 b.Furthermore, portions 2783 a and 2783 b may include any suitable shapeknown in the art. Although portions 2783 a and 2783 b in the illustratedembodiment together define a substantially triangular shaped electrodecontact 2783, portions 2783 a and 2783 b together may or may not defineany suitable shape known in the art.

Each of portions 2783 a and 2783 b may be configured to be substantiallysimilar in conductance despite their differing surface areas. Forexample, portion 2783 a may be made of a first material having arelatively lower conductance, while portion 2783 b may be made of asecond material having a relatively higher conductance. Thus, whensubjected to the same stimulation pulse (e.g., a slow rising, smallamplitude pulse having a relatively long duration of approximately 0.2to 0.35 milliseconds), portion 2783 a may have a higher charge densitythan portion 2783 b because of its relatively smaller surface area thanportion 2783 b. Similarly, when subjected to the same stimulation pulse,portion 2783 b may have a lower charge density than portion 2783 abecause of its relatively larger surface area than portion 2783 a.Accordingly, because of the differing charge densities, portion 2783 amay be adapted to stimulate large diameter fibers of a nerve, andportion 2783 b may be adapted to stimulate small diameter fibers of thenerve.

In use, a stimulation pulse may be first delivered to portion 2783 a tostimulate the large diameter fibers of a nerve. A subsequent stimulationpulse may be then delivered to portion 2783 b to stimulate the smalldiameter fibers of the nerve. It is contemplated that alternatingbetween stimulating the small and large diameter fibers of a nerve mayfacilitate muscle fatigue while also ensuring that sufficient musclemass is stimulated to maintain the necessary contraction and forcegeneration to successfully treat OSA.

In certain embodiments, such as when nerve cuff electrodes 2760 and 2780are implanted on a multi-function nerve (e.g., the superior laryngealnerve SLN), it is contemplated that portions 2763 a/2763 b and portions2783 a/2783 b may be utilized to selectively stimulate either theafferent or efferent fibers of the nerve.

With reference now to FIGS. 27M-27Q, there is depicted yet anotherembodiment of a nerve cuff electrode 2790 for minimizing muscle fatigue.Nerve cuff electrode 2790 may include a cuff body 2791 for mountingabout a nerve 2792 in accordance with the present disclosure. Cuff body2791 may include a plurality of electrode contacts 2793-2796 also inaccordance with the present disclosure. Although the depicted embodimentof nerve cuff electrode 2790 includes four electrode contacts 2793-2796,nerve cuff electrode 2790 may include a greater or lesser number ofelectrode contacts.

Nerve cuff electrode 2790 may be configured to selectively stimulateboth small diameter fibers contained in fascicle 2777 a and largediameter fibers contained in fascicle 2777 b of nerve 2792. For example,as shown in FIG. 27P, by applying an exemplary slow rising, long pulsewidth waveform to electrode contacts 2796 and 2793, nerve cuff electrode2790 may stimulate the small diameter fibers contained in fascicle 2777a of nerve 2792. Similarly, as shown in FIG. 27Q, by applying anexemplary fast rising, short pulse width waveform to electrode contacts2794 and 2795, nerve cuff electrode 2790 may stimulate the largediameter fibers contained in fascicle 2777 b of nerve 2792. Fascicles2777 a and 2777 b may be stimulated simultaneously or separately. Inembodiments, where it is desirable to stimulate fibers contained infascicles 2777 a and 2777 b, the pulse generator (e.g., INS 50) may beprovided with dual output ports.

Description of Respiration Sensing Lead Anchoring Alternatives

With reference to the following figures, various additional oralternative anchoring features for the respiration sensing lead 70 areschematically illustrated. Anchoring the respiration sensing lead 70reduces motion artifact in the respiration signal and stabilizes thebio-impedance vector relative to the anatomy.

In each of the embodiments, by way of example, not limitation, therespiration sensing lead 70 includes a lead body 70 with a proximalconnector and a plurality of distal respiration sensors 74 comprisingring electrodes for sensing bio-impedance. The lead body 72 of therespiration sensing lead 70 may include a jacket cover containing aplurality of conductors 78, one for each ring electrode 74 requiringindependent control. Generally, the impedance electrodes 74 may comprisecurrent emitting electrodes and voltage sensing electrodes for detectingrespiration by changes in bio-impedance.

With reference to FIGS. 28-33, various fixation devices and methods areshown to acutely and/or chronically stabilize the respiratory sensinglead 70. With specific reference to FIG. 28, the INS 50 is shown in asubcutaneous pocket and the stimulation lead 60 is shown in asubcutaneous tunnel extending superiorly from the pocket. Therespiration sensing lead 70 is shown in a subcutaneous tunnelsuperficial to muscle fascia around the rib cage. A suture tab or ring270 may be formed with or otherwise connected to the distal end of thelead body 72. Near the distal end of the lead 70, a small surgicalincision may be formed to provide access to the suture tab 270 and themuscle fascia under the lead 70. The suture tab 270 allows the distalend of the lead 70 to be secured to the underlying muscle fascia bysuture or staple 272, for example, which may be dissolvable orpermanent. Both dissolvable and permanent sutures/staples provide foracute stability and fixation until the lead body 72 is encapsulated.Permanent sutures/staples provide for chronic stability and fixationbeyond what tissue encapsulation otherwise provides.

With reference to FIGS. 29A-29C, a fabric tab 280 may be used in placeof or in addition to suture tab 270. As seen in FIG. 29A, the fabric tab280 may be placed over a distal portion of the lead body 72, such asbetween two distal electrodes 74. A small surgical incision may beformed proximate the distal end of the lead 70 and the fabric tab 280may be placed over the over the lead body 72 and secured to theunderlying muscle fascia by suture or staple 282, for example, which maybe dissolvable or permanent, to provide acute and/or chronic stabilityand fixation. With reference to FIGS. 29B and 29C (cross-sectional viewtaken along line A-A), the fabric tab 280 may comprise a fabric layer(e.g., polyester) 284 to promote chronic tissue ingrowth to the musclefascia and a smooth flexible outer layer (silicone or polyurethane) 286for acute connection by suture or staple 282.

With reference to FIG. 30, lead 70 includes a split ring 290 that may beformed with or otherwise connected to the distal end of the lead body72. The split ring 290 allows the distal end of the lead 70 to besecured to the underlying muscle fascia by suture or staple 292, forexample, which may be dissolvable or permanent. The ring 290 may beformed of compliant material (e.g., silicone or polyurethane) and mayinclude a slit 294 (normally closed) that allows the lead 70 to beexplanted by pulling the lead 70 and allowing the suture 292 to slipthrough the slit 294, or if used without a suture, to allow the ring todeform and slide through the tissue encapsulation. To further facilitateexplanation, a dissolvable fabric tab 282 may be used to acutelystabilize the lead 70 but allow chronic removal.

With reference to FIGS. 31A-31C, deployable anchor tines 300 may be usedto facilitate fixation of the lead 70. As seen in FIG. 31A, theself-expanding tines 300 may be molded integrally with the lead body 72or connected thereto by over-molding, for example. The tines 300 maycomprise relatively resilient soft material such as silicone orpolyurethane. The resilient tines 300 allow the lead 70 to be deliveredvia a tubular sheath or trocar 304 tunneled to the target sensing site,wherein the tines 300 assume a first collapsed delivery configurationand a second expanded deployed configuration. As seen in FIGS. 31B and31B, the tubular sheath or trocar 304 may be initially tunneled to thetarget site using an obtruator 306 with a blunt dissection tip 308.After the distal end of the tubular sheath 304 has been tunneled intoposition by blunt dissection using the obtruator 306, the obtruator 306may be removed proximally from the sheath 304 and the lead 70 withcollapsible tines 300 may be inserted therein. As seen in FIG. 31C, whenthe distal end of the lead 70 is in the desired position, the sheath 304may be proximally retracted to deploy the tines 300 to engage the musclefascia and adjacent subcutaneous tissue, thus anchoring the lead 70 inplace.

With reference to FIGS. 32A and 32B, an alternative deployable fixationembodiment is shown schematically. In this embodiment, self-expandingtines 310 are held in a collapsed configuration by retention wire 312disposed in the lumen of the lead body 72 as shown in FIG. 32A. Each ofthe tines 310 includes a hole 314 through which the retention wire 312passes to hold the tines 310 in a first collapsed delivery configurationas shown In FIG. 32A, and proximal withdrawal of the retention wire 314releases the resilient tines 310 to a second expanded deployedconfiguration as shown in FIG. 32B. The lead 70 may be tunneled to thedesired target site with the tines 310 in the collapsed configuration.Once in position, the wire 312 may be pulled proximally to release thetines 310 and secure the lead 70 to the underlying muscle fascia andadjacent subcutaneous tissue to establish fixation thereof.

With reference to FIGS. 33A and 33B, another alternative deployablefixation embodiment is shown schematically. In this embodiment,self-expanding structures such as one or more resilient protrusions 320and/or a resilient mesh 325 may be incorporated (either alone or incombination) into the distal end of the lead 70. By way of example, notlimitation, resilient protrusions 320 may comprise silicone orpolyurethane loops and resilient mesh 325 may comprise a polyesterfabric connected to or formed integrally with the lead body 72. Both theresilient protrusions 320 and the resilient mesh 325 may be delivered ina collapsed delivery configuration inside tubular sheath 304 as shown inFIG. 33A, and deployed at the desired target site by proximal retractionof the sheath 304 to release the self-expanding structures 320/325 to anexpanded deployed configuration as shown in FIG. 33B. Both the resilientprotrusions 320 and the resilient mesh 325 engage the underlying musclefascia through tissue encapsulation and adjacent subcutaneous tissues toprovide fixation of the lead 70 thereto.

Other fixation embodiments may be used as well. For example, thefixation element may engage the muscle fascia and adjacent subcutaneoustissues or may be embedded therein. To this end, the electrodes mayalternatively comprise intramuscular electrodes such as barbs or helicalscrews.

Description of Respiration Sensing Electrode Alternatives

A description of the various alternatives in number, spacing, anatomicallocation and function of the impedance electrodes follows. Generally, ineach of the following embodiments, the respiration sensing lead includesa lead body and a plurality of respiration sensors comprising ringelectrodes for sensing bio-impedance. The lead body may include aplurality of insulated conductors disposed therein, with one conductorprovided for each ring electrode requiring independent connection and/orcontrol. The impedance electrodes may comprise current emittingelectrodes and voltage sensing electrodes for detecting respiration bychanges in bio-impedance.

With reference to FIG. 34, the distal portion of a respiration sensinglead 70 is shown by way of example, not limitation. The respirationsensing lead 70 includes a lead body 72 with a proximal connector and aplurality of distal impedance electrodes 74. In this example, the leadbody 72 and electrodes 74 are cylindrical with a diameter of 0.050inches. The distal current-carrying electrode 74A may be 5 mm long andmay be separated from the voltage-sensing electrode 74B by 15 mm. Thedistal voltage sensing electrode may be 5 mm long and may be separatedfrom the proximal combination current-carrying voltage-sensing electrode74C by 100 mm. The proximal electrode 74C may be 10 mm long. Theproximal portion of the lead 70 is not shown, but would be connected tothe INS (not shown) as described previously. The lead body incorporatesa plurality of insulated electrical conductors (not shown), each ofwhich correspond to an electrode 74A-74C. The electrodes and conductorsmay be made of an alloy of platinum-iridium. The lead body 72 maycomprise a tubular extrusion of polyurethane, silicone, or aco-extrusion of polyurethane over silicone. The conductors may be formedof multi-filar wire coiled to provide extensibility for comfort anddurability under high-cycle fatigue.

With reference to FIGS. 35A-35E, the position of the electrodes 74 maybe characterized in terms of bio-impedance or bio-Z vectors. The bio-Zvector may be defined by the locations of the voltage-sensing electrodes(labeled V₁ & V₂). The voltage-sensing electrodes may be located oneither side of the current-carrying electrodes (labeled I₁ & I₂). Forexample, it is possible to locate either one or both of thevoltage-sensing electrodes between the current-carrying electrodes asshown in FIG. 35A (4-wire configuration (I₁-V₁-V₂-I₂)), and it ispossible to locate either one or both of the current-carrying electrodesbetween the voltage-sensing electrodes as shown in FIG. 35B (inverted4-wire configuration (V₁-I₁-I₂-V₂)). While at least two separateelectrodes & I₂) are required to carry current and at least two separateelectrodes (V₁ & V₂) are required to measure voltage, it is possible tocombine the current carrying and voltage sensing functions in a commonelectrode. Examples of combining voltage sensing and current carryingelectrodes are shown in FIGS. 35C-35E. FIG. 35C (2-wire configuration(I₁V₁-I₂V₂)) shows combination electrode I₁V₁ and I₂V₂ where each ofthese electrodes is used to carry current and sense voltage. FIG. 35D(3-wire configuration (I₁-V₁-I₂V₂)) and 35E (inverted S-wireconfiguration (V₁-I₁-I₂V₂)) show combination electrode I₂V₂ which isused to carry current and sense voltage.

With reference to FIG. 36, insulative material such as strips 73 maycover one side of one or more electrodes 74A-74D to provide directionalcurrent-carrying and/or voltage-sensing. The insulative strips maycomprise a polymeric coating (e.g., adhesive) and may be arranged toface outward (toward the dermis) such that the exposed conductive sideof each electrode 74 faces inward (toward the muscle fascia and thoraciccavity). Other examples of directional electrodes would be substantiallytwo-dimensional electrodes such as discs or paddles which are conductiveon only one side. Another example of a directional electrode would be asubstantially cylindrical electrode which is held in a particularorientation by sutures or sutured wings. Another example of adirectional electrode would be an electrode on the face or header of theimplanted pulse generator. It would likely be desirable for the pulsegenerator to have a non-conductive surface surrounding the location ofthe electrode.

In addition to the cylindrical electrodes shown, other electrodeconfigurations are possible as well. For example, the electrodes may bebi-directional with one planar electrode surface separated from anotherplanar electrode surface by insulative material. Alternatively or incombination, circular hoop electrodes may be placed concentrically on aplanar insulative surface. To mitigate edge effects, each electrode maycomprise a center primary electrode with two secondary side electrodesseparated by resistive elements and arranged in series. An alternativeis to have each primary current-carrying electrode connected by aresistive element to a single secondary side electrode. The conductivehousing of the INS 50 may serve as an current-carrying electrode orvoltage-sensing electrode. Alternatively or in addition, an electrodemay be mounted to the housing of the INS 50.

Because bio-impedance has both a real and imaginary component, it ispossible to measure the bio-Z phase as well as magnitude. It may bepreferable to extract both magnitude and phase information from thebio-Z measurement because the movement of the lung-diaphragm-liverinterface causes a significant change in the phase angle of the measuredimpedance. This may be valuable because motion artifacts of other tissuehave less impact on the bio-Z phase angle than they do on the bio-Zmagnitude. This means the bio-Z phase angle is a relatively robustmeasure of diaphragm movement even during motion artifacts.

An example of a bio-Z signal source is a modulated constant-currentpulse train. The modulation may be such that it does not interfere withthe stimulation signal. For example, if the stimulation signal is 30 Hz,the bio-Z signal source signal may be modulated at 30 Hz or asub-multiple of 30 Hz such that bio-Z and stimulation do not occursimultaneously. The pulses in the pulse train may have a pulse widthbetween 1 uS to 1 mS, such as 100 uS or 10 uS. The pulses may beseparated by a period of time roughly equal to the pulse width (i.e.,on-time of the pulses). The number of pulses in a train may bedetermined by a trade-off between signal-to-noise and power consumption.For example, no more than 100 pulses or no more than 10 pulses may benecessary in any given pulse train. The magnitude of current deliveredduring the pulse on-time may be between 10 uA and 500 uA, such as 50 uA.

Other wave forms of bio-Z source signal may be used, including, withoutlimitation, pulse, pulse train, bi-phasic pulse, bi-phasic pulse train,sinusoidal, sinusoidal w/ramping, square wave, and square w/ramping. Thebio-Z source signal may be constant current or non-constant current,such as a voltage source, for example. If a non-constant current sourceis used, the delivered current may be monitored to calculate theimpedance value. The current-carrying electrodes may have a singlecurrent source, a split-current source (one current source split betweentwo or more current-carrying electrodes), or a current mirror source(one current source that maintains set current levels to two or morecurrent-carrying electrodes). Different characteristics of the sensedsignal may be measured including, without limitation, magnitude, phaseshift of sensed voltage relative to the current source signal, andmulti-frequency magnitude and/or phase shift of the sensed signal.Multi-frequency information may be obtained by applying multiple signalsources at different frequencies or a single signal source whichcontains two or more frequency components. One example of a singlemulti-frequency source signal is a square wave current pulse. Theresultant voltage waveform would contain the same frequency componentsas the square wave current pulse which would allow extraction of Bio-Zdata for more than a single frequency.

With reference to FIG. 37, the bio-Z vector may be oriented with regardto the anatomy in a number of different ways. For example, using theelectrode arrangement illustrated in FIG. 34 and the anatomicalillustration in FIG. 37, the bio-Z vector may be arranged such that theproximal combination electrode is located just to the right of and abovethe xiphoid below the pectoral muscle between the 5th and 6th ribs andthe distal current-carrying electrode is located mid-lateral between the7th and 8th ribs, with the distal voltage-sensing electrode positionedbetween the 6th and 7th ribs 10 mm proximal of the distalcurrent-carrying electrode. This arrangement places the electrodes alongthe interface between the right lung, diaphragm and liver on the rightside of the thoracic cavity. The lung-diaphragm-liver interface movesrelative to the bio-Z vector with every respiratory cycle. Because thelung has relatively high impedance when inflated and the liver hasrelatively low impedance due to the conductivity of blood therein, thisbio-Z vector arrangement across the lung-diaphragm-liver interfaceprovides for a strong respiratory signal that is indicative of changesbetween inspiration and expiration. In addition, because the heart issituated more on the left side, positioning the bio-Z vector on theright side reduces cardiac artifact. The net result is a bio-Z vectorthat provides an excellent signal-to-noise ratio.

A variety of different bio-Z vector orientations relative to the anatomymay be employed. Generally, bio-Z vectors for monitoring respiration maybe located on the thorax. However, bio-Z electrodes located in the headand neck may also be used to define respiratory bio-Z vectors. By way ofexample, not limitation, the bio-Z vector may be arrangedtransthoracically (e.g., bilaterally across the thorax), anteriorly onthe thorax (e.g., bilaterally across the thoracic midline), across thelung-diaphragm-liver interface, perpendicular to intercostal muscles,between adjacent ribs, etc. A single bio-Z vector may be used, ormultiple independent vectors may be used, potentially necessitatingmultiple sensing leads. One or more bio-Z sub-vectors within a givenbio-Z vector may be used as well.

With reference to FIGS. 37A-37C, thoracic locations defining examples ofbio-Z vectors are shown schematically. FIGS. 37A and 37D are frontalviews of the thorax, FIG. 37B is a right-side view of the thorax, andFIG. 37C is a left-side view of the thorax; In each of FIGS. 37A-37D,the outline of the lungs and upper profile of the diaphragm are shown.As mentioned previously, a bio-Z vector may be defined by the locationsof the voltage-sensing electrodes. Thus, FIGS. 37A-37D show locationsfor voltage sensing electrodes which would define the bio-Z vector.

There are several short bio-Z vectors which provide excellent signalscorrelated to diaphragmatic movement. In general, these vectors have atleast one end at or near the lower edge of the ribcage. The shortdiaphragmatic bio-Z vectors have been successfully used in canines invector lengths ranging from approximately less than ½ inch to a fewinches in length. FIG. 37A shows a variety of locations which arerepresentative of the locations which define such vectors. Locationsshown just below the ribcage on the person's right side are designatedas A, B, C, and D. Locations shown just below the ribcage on theperson's left side are E, F, G, and H. Locations shown just above thelower edge of the ribcage on the person's right side are I, J, K, and L.Locations shown just above the lower edge of the ribcage on the person'sleft side are M, N, P, and Q. The locations just above the lower edge ofthe ribcage would fall within a few inches of the lower edge. Shortdiaphragmatic monitoring vectors would be comprised of location pairswhich are relatively closely spaced. For example, vectors D-E, D-C, D-L,and D-K all provide good diaphragmatic signal. The possible vectors fallinto three groups. Exemplary vectors which measure primarilydiaphragmatic muscle contraction are A-B, B-C, C-D, D-E, E-F, F-G, andG-H. Exemplary vectors which measure a combination of diaphragmaticmuscle contraction combined with movement of the lung into the pleuralpocket as the diaphragm contracts are I-J, P-R, A-I, A-J, B-I, B-J, G-P,H-R, H-P, and G-R. Exemplary vectors which measure diaphragmatic musclecontraction combined with movement of the diaphragm away from thethoracic wall as that portion of the lung expands are J-K, K-L, M-N, andN-P. It is known that the signal from any given location may be affectedby body position and free vs. obstructed respiration. The respiratorysignal from short vectors at or near the lower edge of the ribcage maybe more robust (e.g., may be not be substantially affected) to bodyposition and obstructed respiration. A further means of obtaining asignal which may be also more robust to body position would be tomeasure the respiratory impedance from complimentary vectors and sum theresulting bio-Z measurements. Complimentary vectors would bemirror-images or nearly mirror images of one another. Examples ofvectors and their mirror images may be C-D and E-F, B-C and G-F, C-K andF-N.

By way of example, not limitation, the following bio-Z vectors may beeffective for monitoring respiration and/or for measuring artifacts forsubsequent removal of the artifact from the respiration signal. VectorC-G is across the upper left and upper right lobes of the lungs, andprovides a good signal of ribcage expansion with moderate cardiacartifact. Vector D-F is a short-path version of C-G that provides a goodrespiratory signature largely correlated with ribcage expansion, withless cardiac artifact than C-G, but may be sensitive to movement of armsdue to location on pectoral muscles. Vector C-D is a short-pathipsilateral vector of the upper right lung that may be sensitive to armmovement but has less cardiac artifact. Vector B-H is a transversevector of the thoracic cavity that captures the bulk of the lungs anddiaphragm movement. Vector B-H, however, may be relatively lesssusceptible to changes in body position, and may still provide agenerally good signal when the patient changes positions. In certaincircumstances, the signal produced by vector B-H may have a less thandesired signal to noise ratio. However, it is contemplated thatgenerally available methods of signal processing in accordance with thepresent disclosure may be utilized the improve signal to noise ratio ofthe signal produced by Vector B-H. Vector A-E is an ipsilateral vectoracross the lung-diaphragm-liver interface. Because the liver is higherin conductivity and has a different impedance phase angle than the lung,vector A-E1 yields a good signal on both bio-Z magnitude and phase withlimited cardiac artifact. Vector B-K is an ipsilateral vector across thelung-diaphragm-liver interface that is substantially between a commonset of ribs with a current path that is mostly perpendicular to theintercostal muscles. Because resistivity of muscle is much higherperpendicular to the muscle direction than parallel, vector B-K reducescurrent-shunting through the muscle which otherwise detracts from thesignal of the lung-diaphragm-liver interface. Vector A-K is anipsilateral vector across the lung-diaphragm-liver interface similar tovector A-E1 but is more sensitive to movement of thelung-diaphragm-liver interface than to changes in resistivity of thelung-diaphragm-liver interface due to inspired air volume and is thus agood indicator of diaphragm movement. Vector B-E1 is a vector across themiddle and lower right lung and is good for detecting diaphragm movementwith little cardiac artifact. Vector C-E1 is a vector across the upperand middle right lung and is also good for detecting diaphragm movementwith little cardiac artifact. Vector D-E1 is a vector across the upperright lung with little cardiac artifact. Vector A-D is an ipsilateralacross a substantial portion of the right lung and diaphragm with littlecardiac artifact, but may be susceptible to motion artifact due to armmovement. Vector E1-E2 is a vector across the heart and provides a goodcardiac signal that may be used for removing cardiac artifact from arespiratory signal. Vector E2-J is a vector across thelung-diaphragm-stomach interface that provides a good measure ofdiaphragm movement using bio-Z phase vs. magnitude because the stomachhas almost no capacitive component and generally low conductivity.Vector L-M is a trans-diaphragm vector that is generally across thelung-diaphragm-liver interface with little cardiac artifact. Vector L-Mmay be relatively less susceptible to body position and movement and mayyield a good signal even if the patient is laying on the side of thesensing lead. In embodiments where the signal produced by vector L-M hasa less than desired signal to noise ratio, it is contemplated thatgenerally available methods of signal processing may be utilized toimprove the signal to noise ratio of the signal produced by vector L-M.

Electrodes placed at any of the above-noted locations may include, butare not limited to, combination electrodes, such as, for example,electrodes capable of both providing a current charge and sensing avoltage.

With reference to FIGS. 37A and 38D, an exemplary vector selectionmethod 3800 for detecting and utilizing a signal from the vector thatproduces the most desirable signal of all vectors is discussed. Thedisclosed vector selection method 3800 may be performed continuously,periodically, singularly, and/or may be repeated as desired. Forexample, method 3800 may be performed once in a 24 hour period. Inaddition, one or more steps associated with method 3800 may beselectively omitted and/or the steps associated with method 3800 may beperformed in any order. The steps associated with method 3800 aredescribed in a particular sequence for exemplary purposes only.

With specific reference to FIG. 38D, method 3800 may include a pluralityof steps 3801-3803 for detecting and utilizing the signal with the bestcharacteristics of all signals produced by a plurality of vectors.Specifically, method 3800 may include sampling short distance vectorsfirst to determine if any of these vectors are producing a desirablesignal, step 3801. Method 3800 may also include sampling intermediatedistance vectors if the short distance vectors are not producing adesirable signal, step 3802. Method 3800 may further include samplinglong distance vectors if the intermediate distance vectors are notproducing a desirable signal, step 3803.

Turning to FIG. 37A, there is depicted an exemplary embodiment of aneurostimulator in accordance with the principles of the presentdisclosure. The exemplary neurostimulator may include an implanted INS50 and implanted electrode contacts AA-DD. While the depicted embodimentincludes electrode contacts AA-DD disposed between a patient's 5th andlowest ribs, electrode contacts AA-DD may be disposed at any suitablelocation. Furthermore, electrode contacts AA-DD may include, but are notlimited to, the combination electrodes discussed above. In the depictedembodiment, exemplary short distance vectors may include the vectorsbetween, for example, adjacent electrode contacts AA, BB, CC, and DD;exemplary intermediate distance vectors may include the vectors AA-CC,AA-DD, and BB-DD, and exemplary long distance vectors may include thevectors between the INS 50 and each of electrode contacts AA-DD.

With reference to FIG. 37A and FIG. 38A, step 3801 may include, forexample, sampling short distance vectors AA-BB, BB-CC, and CC-DD firstto determine whether any of these vectors may be producing a sufficientsignal in accordance with the principles of this disclosure, since thesevectors generally produce signals with desirable signal to noise ratios.Next, step 3802 of method 3800 may include sampling the intermediatedistance vectors AA-CC, AA-DD, and BB-DD if the short distance vectorsare producing a less than desirable signal. Lastly, step 3803 of method3800 may include sampling the long distance vectors INS-AA, INS-BB,INS-CC, and INS-DD if the intermediate distance vectors are producing aless than desirable signal.

In some embodiments, it is contemplated that several short,intermediate, and long distance vectors may be continually sampled, evenif a desirable signal is being received from a short distance vector, inorder to identify secondary vector signals that may be utilized if thecurrently utilized vector signal fails for any reason. However, fullyprocessing the data from signals generated by all of the vectors mayrequire complex sensing circuitry and processing of detection algorithmsthat may utilize undesirable amounts of battery power. Therefore, it maybe desirable to only monitor selected characteristics of the secondaryvector signals. With specific reference to FIG. 38B, there is depictedan embodiment of a method 3850 for utilizing multiple sensing channelsto optimize respiratory sensing with minimal additional hardware andpower consumption. It uses a single sensing circuit which is timemultiplexed (interleaved) to sample each of the vectors. Since, as notedabove, fully processing the data from all vector signals may requirehigher computational power, method 3850 may be used to identify the bestvector signal for respiration detection, while simultaneously monitoringthe remaining vectors signals for only relevant fiducial points. Thesefiducial points may include, but are not limited to, significant“landmarks” within a signal, such as, for example, peak amplitude andtime, point of highest slew rate, and zero crossing. The detectedfiducial points for the secondary vector signals may be then stored in acircular buffer memory 3854 for analysis if the primary signal fails forany reason, thereby, allowing immediate switching to an alternate vectorsignal and eliminating the need for a long signal acquisition periodafter a need to switch vector signals has been determined.

In particular, method 3850 may include feeding the signals from allavailable vectors into a plurality of channel selection switches 3851.The signals may be then analyzed for relevant fiducials by therespiratory impedance sensing circuit 3853. Once relevant fiducials havebeen discriminated, it may be possible to identify the best vectorsignal for respiration signal analysis. The fiducials of the remainingvectors may be then stored in circular buffer memory 3854 (as notedabove) to facilitate switching to a secondary vector signal if theprimary signal is no longer suitable for respiration detection.

The periodic monitoring (or interleaving) of secondary vector signalsmay facilitate faster switching to those vector signals when necessary.In particular, it is contemplated that when a decision to switch to asecondary vector signal is made (i.e., when the primary signals degradesto a point where it is no loner desirable for detecting respiration),the saved data (e.g., relevant fiducials) may be used to “seed” a signalanalysis algorithm with recently collected data, so as to promote fastervector switching by eliminating the need to wait for collection ofsufficient data for the secondary vector signal. In other words, becauseselect information of a secondary signal is available before the signalis actually used for respiration detection, analysis of the secondarysignal for, among other things, respiration detection may begin slightlyfaster than it would have if no data was available.

Furthermore, in certain embodiments, additional impedance sensors may beused as backup sensors to the sensor generating the primary vectorsignal. In these embodiments, data from the secondary sensors may bealso analyzed to identify and save relevant fiducials in the memory.This stored information may be used to provide supplemental or alternateinformation to facilitate identifying appropriate respiratory timing,when switching vector signals becomes necessary as a result of primarysignal degradation.

The respiratory bio-Z signal is partly due to the resistivity changewhich occurs when air infuses lung tissue, partly due to the relativemovement of electrodes as the rib cage expands, and partly due to thedisplacement of other body fluids, tissue and organs as the lungs movealong with the ribcage and diaphragm. As described above, each vectormeasures certain of these changes to different extents. It may bedesirable, therefore, to combine vectors which have complementaryinformation or even redundant information to improve the respiratoryinformation of the bio-Z signal. To this end, multiple vectors may beused. For example, one vector may be used to sense changes in thelung-diaphragm-liver interface and a second vector may be used to detectchanges (e.g., expansion, contraction) of the lung(s). Examples of theformer include A-K, B-K, A-E1, B-E1, and A-B. Examples of the laterinclude D-F, B-D, C-G, D-E1, and C-E1. Note that some vectorcombinations which share a common vector endpoint such as A-E1, D-E1 andB-E1, B-D may use a common electrode which would simplify therespiratory sensing lead or leads.

An advantage of using the lung-diaphragm-liver interface vector is thatit provides a robust signal indicative of the movement of the diaphragmthroughout the respiratory cycle. The liver is almost two times moreelectrically conductive than lung tissue so a relatively large bio-Zsignal can be obtained by monitoring the movement of thelung-diaphragm-liver interface. Because the liver functions to filterall the blood in the body, the liver is nearly completely infused withblood. This helps to dampen out the cardiac artifact associated with thepulsatile flow of the circulatory system. Another advantage of thislocation is that vectors can be selected which avoid significant currentpath through the heart or major arteries which will help reduce cardiacartifact.

It is worth noting that diaphragm movement is not necessarilysynchronous with inspiration or expiration. Diaphragm movement typicallycauses and therefore precedes inspiration and expiration. Respiratorymechanics do allow for paradoxical motion of the ribcage and diaphragm,so diaphragm movement is not necessarily coincident with inspiration.During REM sleep, the diaphragm is the dominant respiratory driver andparadoxical motion of the ribs and diaphragm can be problematic,especially if movement of the ribcage is being relied upon as aninspiratory indicator. Monitoring the diaphragm for pre-inspiratorymovement becomes especially valuable under these circumstances. Bio-Zmonitoring of the diaphragm can be used as a more sophisticatedindicator of impending inspiration rather than the antiquated approachof desperately trying to identify and respond to inspiration inpseudo-real time based on sensors which are responding tocharacteristics of inspiration.

For purposes of monitoring respiration, it is desirable to minimizeshunting of the electrical current through tissues which are not ofinterest. Shunting may result in at least two problems: reduced signalfrom the lungs; and increased chance of artifacts from the shuntedcurrent path. Skeletal muscle has non-isotropic conductivity. Themuscle's transverse resistivity (1600 ohm-cm) is more than 5 times itslongitudinal resistivity (300 ohm-cm). In order to minimize the adverseeffect of shunting current, it is desirable to select bio-Z sensingvectors which are perpendicular to muscle structure if possible. Onesuch example is to locate two or more electrodes of a bio-Z sensingarray substantially aligned with the ribs because the intercostalmuscles are substantially perpendicular to the ribs.

Description of Respiration Signal Processing

With reference to FIG. 39, the neurostimulation system described hereinmay operate in a closed-loop process 400 wherein stimulation of thetargeted nerve may be delivered as a function of a sensed feedbackparameter (e.g., respiration). For example, stimulation of thehypoglossal nerve may be triggered to occur during the inspiratory phaseof respiration. Alternatively, the neurostimulation system describedherein may operate in an open-loop process wherein stimulation isdelivered as a function of preset conditions (e.g., historical averageof sleeping respiratory rate).

With continued reference to FIG. 39, the closed-loop process 400 mayinvolve a number of generalized steps to condition the sensed feedbackparameter (e.g., bio-Z) into a useable trigger signal for stimulation.For example, the closed-loop process 400 may include the initial step ofsensing respiration 350 using bio-Z, for example, and optionally sensingother parameters 360 indicative of respiration or other physiologicprocess. The sensed signal indicative of respiration (or otherparameter) may be signal processed 370 to derive a usable signal anddesired fiducials. A trigger algorithm 380, which will be discussed ingreater detail below, may then be applied to the processed signal tocontrol delivery of the stimulation signal 390.

As noted above, the present disclosure contemplates conditioning sensedbio-impedance into a useable trigger signal for stimulation. However,one exemplary limitation to using sensed bio-impedance may be the body'snominal impedance. In practice, a sensed bio-impedance signal may beobtained by applying a suitable, known current through one portion of atissue of interest and measuring the voltage potential across the sametissue. This measurement technique is illustrated in FIG. 38C and may bereferred to herein as the “direct measurement” technique. The appliedcurrent and measured voltage potentials may be used to calculate theimpedance of the tissue. It is this measured impedance that mayconstitute the sensed bio-impedance signal. However, sense bio-impedancesignals of the present disclosure have been found to typically includetwo components, a relatively large nominal body impedance component anda relatively small respiratory impedance component. Thus, since thebody's impedance constitutes a large portion of the sensed signal, itmay be difficult to detect that relatively small impedance changesassociated with respiration on top of a body's nominal impedance.Therefore, in accordance with the principles of the present disclosure,it may be desirable to “filter” the sensed impedance signal in a mannerso as to remove most or all of the body's nominal impedance, in order toimprove resolution of the respiratory signal. In some embodiments, thismay be achieved with the aid of a conventional Wheatstone bridge at ornear the front-end of an impedance measuring circuit. In particular, theWheatstone bridge may facilitate precise measurements of the relativelysmall impedance changes associated with respiration by removing most, ifnot all, of the body's nominal impedance.

Turning now to FIG. 39A, there is depicted an exemplary Wheatstonebridge 3900. The Wheatstone bridge 3900 may include an electricalcurrent source 3901. Wheatstone bridge 3900 may also include a firstresistor R₁ having an impedance Z₁ connected in series to a secondresistor R₂ having an impedance Z₂. Resistors R₁ and R₂ may be connectedin parallel to resistor R₃ having an impedance Z₃, which may beconnected serially to the patient's body having an impedance Z_(body).As discussed below, impedances Z₂ and Z₃ may be substantially similar toeach other. Wheatstone bridge 3900 may further include any suitablevoltage measuring device, such as, for example, those used inconjunction the direct measurement technique described above.

In use, the impedance Z₁ of exemplary bridge 3900 may be closely matchedto the expected impedance of a patient's body Z_(body), the impedance Z₂matched to impedance Z₃, and the voltage potential across voltagemeasuring device 3902 may be measured. It is contemplated that ifimpedances Z₁-Z₃ are closely matched to Z_(body), the measured voltagepotential across voltage measuring device 3902 will be predominantly dueto respiratory impedance changes and the voltage signal due to thebody's nominal impedance will be largely removed. Further, it iscontemplated that the voltage changes measured at 3902 due torespiratory impedance changes will have an amplitude that isapproximately ½ of the amplitude of the voltage changes, measured withthe above-noted direct-measurement technique, assuming the samecurrently flow through the body. The removal of the voltage signal dueto the body's nominal impedance while retaining ½ of the voltage signalamplitude due to changes in respiratory impedance, may facilitatedetecting the small impedance changes associated with respiration byimproving the resolution of those changes.

In other embodiments, the body's nominal impedance may be removed orreduced from a sensed signal by, for example, introducing a nominaloffset removal module 3921 into an impedance measuring circuit 3920 ofthe present disclosure, as depicted in FIG. 39B. An exemplaryimpedance-measuring circuit may generally include feeding a sensedrespiratory signal into a demodulator. The signal exiting thedemodulator may be then fed into an integrator, and the integratedsignal exiting the integrator may then be digitized for analysis. It istherefore contemplated that introducing nominal offset removal module3921 to act upon the upon the signal exiting the demodulator may achievethe desired effect of removing or reducing the body's nominal impedancefrom a sensed impedance signal.

Turning now to FIG. 39C, module 3921 may include a switch S, a resistorR, a capacitor C, and a non-inverting amplifier A. The switch S,resistor R, and capacitor C create a sample and hold reference voltageto the difference amplifier A. The amplifier subtracts this referencevoltage from the input signal. The result is to remove or reduce thenominal body impedance component of the signal leaving mainly therespiratory component of the measured impedance. The Resistor-Capacitor(R-C) combination is selected such that it will track with changes innominal impedance levels but does not significantly distort therespiratory signal. Respiratory signal frequency components of interestare typically between 0.05 Hz and 3 Hz. There are several options forhow the Nominal Offset Removal may be operated. An implantedbio-impedance circuit would typically use a modulated excitation signalfor measuring impedance. In that case, the switch, S may be open whenthere is no signal present and may be closed whenever a signal ispresent. For example, if a Demodulator Signal is present for 1 ms every100 ms, switch S would be closed during all or a part of the time thatSignal In is present. Switch S may also be operated such that it doesnot close on every instance when Demodulator Signal is present. Theswitch S, may be closed on every 10^(th) or 100^(th) instance whenDemodulator Signal is present. A third possibility is to close switch Sonly when Signal Out causes the Integrator to reach an unacceptablethreshold. The integrator reaching an unacceptable threshold may beindicative that the reference voltage provided by the R-C combination isno longer providing a sufficiently good estimate of the nominal signalcomponent and so needs to be updated with new information.

Turning now to FIG. 39D, there is depicted an alternative embodiment ofnominal offset removal module. A further improvement on the NominalOffset Removal module is shown in FIG. 39D. If it is desired to measuretwo or more different impedance signals it will be necessary to have adifferent nominal offset reference voltage provided to amplifier A foreach signal. It is also desirable to keep the component count as low aspossible. In the diagram below, S0 and S1 may be closed and S2 may beopen to provide an offset reference for a first signal with theappropriate combination of R-C1. S0 and S2 may be closed and S1 may beopen to provide an offset reference for a second signal with theappropriate combination of R-C2. This strategy allows rapid sequentialmeasurement of two or more impedance signals.

With reference to FIG. 40, the signal processing step 370 may includegeneral signal amplification and noise filtering 372. The step ofamplification and filtering 372 may include band pass filtering toremove DC offset, for example. The respiratory waveform may then beprocessed to remove specific noise artifacts 374 such as cardiac noise,motion noise, etc. A clean respiratory waveform may then be extracted376 along with other waveforms indicative of specific events such asobstructive sleep apnea (OSA), central sleep apnea (CSA), hypopnea,sleep stage, etc. Specific fiducial points may then be extracted andidentified (e.g., type, time, and value).

The step of removing specific noise artifacts 374 may be performed in anumber of different ways. However, before signal processing 374, bothcardiac and motion noise artifact may be mitigated. For example, bothcardiac and motion noise artifact may be mitigated prior to signalprocessing 374 by selection of bio-Z vectors that are less susceptibleto noise (motion and/or cardiac) as described previously. In addition,motion artifact may be mitigated before signal processing 374 byminimizing movement of the sensing lead and electrodes relative to thebody using anchoring techniques described elsewhere herein. Furthermore,motion artifact may be mitigated prior to signal processing 374 byminimizing relative movement between the current-carrying electrodes andthe voltage-sensing electrodes, such as by using combinedcurrent-carrying and voltage-sensing electrodes.

After cardiac and motion artifact has been mitigated using thepre-signal processing techniques described above, both cardiac andmotion artifact may be removed by signal processing 374.

For example, the signal processing step 374 may involve the use of a lowpass filter (e.g., less than 1 Hz) to remove cardiac frequency noisecomponents which typically occur at 0.5 to 2.0 Hz, whereas restingrespiration frequency typically occurs below 1.0 Hz.

Alternatively, the signal processing step 374 may involve the use of aband pass or high pass filter (e.g., greater than 1 Hz) to obtain acardiac sync signal to enable removal of the cardiac noise from thebio-Z signal in real time using an adaptive filter, for example.Adaptive filters enable removal of noise from a signal in real time, andan example of an adaptive filter is illustrated in FIG. 41. To removecardiac artifact from the bio-Z signal which contains both cardiac noisen(k) and respiratory information s(k), a signal n′(k) that representscardiac noise is input to the adaptive filter and the adaptive filteradjusts its coefficients to reduce the value of the difference betweeny(k) and d(k), removing the noise and resulting in a clean signal ine(k). Notice that in this application, the error signal actuallyconverges to the input data signal, rather than converging to zero.

Another signal processing technique to remove cardiac noise is tocombine signals from two or more bio-Z vectors wherein respiration isthe predominate signal with some cardiac noise. This may also be used toreduce motion artifact and other asynchronous noise. Each of the two ormore signals from different bio-Z vectors may be weighted prior tocombining them into a resultant signal Vw(i). If it is assumed that (a)the respiratory bio-impedance is the largest component in each measuredvector, (b) the non-respiratory signal components in one vector aresubstantially independent of the non-respiratory components in the othervector, and (c) the ratio of the non-respiratory component to therespiratory components in one vector is substantially equal to the sameratio in the other vector, then a simple weighting scheme may be usedwherein each signal is divided by it's historic peak-to-peak magnitudeand the results are added. For example, if M_(A)=historical averagepeak-to-peak magnitude of signal from vector A, M_(B)=historical averagepeak-to-peak magnitude of signal from vector B, V_(A)(i)=data point (i)from vector A, V_(B)(i)=data point (i) from vector B, then the resultantsignal V_(W)(i) (i.e., weighted average of A & B for data point (i)) maybe expressed as V_(W)(i)=V_(A)(i)/M_(A)+V_(B)(i)/M_(B).

Yet another signal processing technique for removing cardiac noise is tosubtract a first signal that is predominantly respiration from a secondsignal that is predominantly cardiac. For example, the first signal maybe from a predominantly respiratory bio-Z vector (e.g., vector B-H) withsome cardiac noise, and the second signal may be from a predominantlycardiac bio-Z vector (e.g., vector E1-E2) with some respiration signal.Each of the two signals from the different bio-Z vectors may be weightedprior to subtracting them. The appropriate weighting may be determined,for example, by calculating the power density spectra in the range of2-4 Hz for a range of weighted differences across at least severalrespiratory cycles. A minimum will occur in the power density spectrafor the weighted averages which are sufficiently optimal.

Motion artifact may be removed by signal processing 374 as well. Motionartifact may be identified and rejected using signal processingtechniques such as monitoring voltage magnitude, testing the correlationof magnitude and phase, and/or testing correlation at two or morefrequencies. Motion artifacts may cause a large change in measuredbio-impedance. A typical feature of motion artifacts is that the voltageswings are much larger than respiration. Another feature is that thevoltage changes are highly erratic. Using these characteristics, whichwill be described in more detail below, motion artifact may be removedfrom the respiration signal.

The step of extracting waveforms indicative of respiration and otherevents 374 may be better explained with reference to FIGS. 42-46 whichschematically illustrate various representative unfiltered bio-Zsignals. FIG. 42 schematically illustrates a bio-Z signal 420 withrepresentative signatures indicative normal respiration (i.e., eventfree) during an awake period 422 and a sleeping period 424. FIG. 43schematically illustrates a bio-Z signal 430 with representativesignatures indicative of normal respiration during sleeping periods 424interrupted by a period of motion 432 (i.e., motion artifact). FIG. 44schematically illustrates a bio-Z signal 440 with representativesignatures indicative of normal respiration during a sleeping period 424followed by periods of hypopnea (HYP) 442 and recovery 444. FIG. 45schematically illustrates a bio-Z signal 450 with representativesignatures indicative of normal respiration during a sleeping period 424followed by periods of obstructive sleep apnea (OSA) 452 and recovery454 (which typically includes an initial gasp 456). FIG. 46schematically illustrates a bio-Z signal 460 with representativesignatures indicative of normal respiration during a sleeping period 424followed by periods of central sleep apnea (CSA) 462 (which typicallyincludes a cessation in breathing 468) and recovery 464.

The step of extracting 374 waveform data indicative of an awake period422 vs. a sleep period 424 from a bio-Z signal 420 may be explained inmore detail with reference to FIG. 42. In addition, the step offiltering 372 waveform data indicative of motion 432 from a bio-Z signal430 may be explained in more detail with reference to FIG. 43. One wayto determine if a person is awake or moving is to monitor thecoefficient of variation (CV) of sequential peak-to-peak (PP) magnitudesover a given period of time. CV is calculated by taking the standarddeviation (or a similar measure of variation) of the difference betweensequential PP magnitudes and dividing it by the average (or a similarstatistic) of the PP magnitudes. N is the number of respiratory cycleswhich occur in the selected period of time.

The CV may be calculated as follows:

${CV} = \frac{{sd}({dPP})}{\overset{\_}{PP}}$ Where${{sd}({dPP})} = \sqrt{\frac{\sum\limits_{i = 1}^{N}\;\left( {{dPP}_{i} - \overset{\_}{dPP}} \right.}{\left( {N - 1} \right)}}$$\overset{\_}{dPP} = \frac{\sum\limits_{i = l}^{N}\;\left( {dPP}_{i} \right)}{(N)}$dPP_(i) = PP_(i + 1) − PP_(i)$\overset{\_}{PP} = \frac{\sum\limits_{i = 1}^{N}\;\left( {PP}_{i} \right)}{(N)}$

Generally, if the CV is greater than 0.20 over a one minute period thenperson is awake. Also generally, if the CV is less than 0.20 over aone-minute period then person is asleep. These events may be flagged forthe step of fiducial extraction 378 wherein data (e.g., event duration,CV, PP range, PPmin, PPmax, etc.) may be time stamped and stored with anevent identifier. If CV is greater than 1.00 over a 20 second periodthen body movement is affecting the bio-Z signal. By way of example, notlimitation, if body movement is detected, then (a) stimulation may bedelivered in an open loop fashion (e.g., based on historical respiratorydata); (b) stimulation may be delivered constantly the same or lowerlevel; or (c) stimulation may be turned off during the period ofmovement. The selected stimulation response to detected movement may bepreset by the physician programmer or by the patient control device.Other stimulation responses may be employed as will be describedhereinafter.

In each of FIGS. 44-46, maximum and minimum peak-to-peak magnitudes(PPmax and PPmin) may be compared to distinguish hypopnea (HYP),obstructive sleep apnea (OSA), and central sleep apnea (CSA) events.Generally, PP values may be compared within a window defined by theevent (HYP, OSA, CSA) and the recovery period thereafter. Alsogenerally, the window in which PP values are taken excludes transitionalevents (e.g., gasp 456, 466). As a general alternative, peak-to-peakphases may be used instead of peak-to-peak magnitude. The hypopnea andapnea events may be flagged for the step of fiducial extraction 378wherein data (e.g., event duration, CV, PP range, PPmin, PPmax, etc.)may be time stamped and stored with an event identifier.

A typical indication of hypopnea (HYP) and apnea (OSA, CSA) events is arecurrent event followed by a recovery. The period (T) of each event(where PP oscillates between PPmax and PPmin and back to PPmax) may beabout 15 to 120 seconds, depending on the individual. The largest PPvalues observed during hypopneas and apneas are usually between 2 and 5times larger than those observed during regular breathing 424 duringsleep. The ratio of the PPmax to PPmin during recurrent hypopnea andapnea events is about 2 or more. During the event and recovery periods(excluding transitional events), PP values of adjacent respiratorycycles do not typically change abruptly and it is rare for the change inPP amplitude to be more than 50% of PPmax. One exception to thisobservation is that some people gasp 456, 466 (i.e., transitional event)as they recover from a CSA or OSA event.

The ratio of successive PP magnitudes during normal (non-event) sleep424 is mostly random. The ratio of successive PP magnitudes during apneaand hypopnea events will tend to be a non-random sequence due to theoscillatory pattern of the PP values. Recurrent apneas and hypopneas maybe diagnosed by applying a statistical test to the sequence ofsuccessive PP ratios.

The step of extracting 374 waveform data indicative of an hypopnea event442 from a bio-Z signal 440 may be explained in more detail withreference to FIG. 44. The ratio of PPmax to PPmin during recurrenthypopneas is typically between 2 and 5. This is in contrast to CSA'swhich have very small PPmin due to the complete cessation of breathing.This results in CSA's having PPmax to PPmin ratios larger than 5.Accordingly, hypopnea events may be detected, identified and flagged forthe step of fiducial extraction 378 wherein data (e.g., event duration,CV, PP range, PPmin, PPmax, etc.) may be time stamped and stored with anevent identifier.

The step of extracting 374 waveform data indicative of an OSA event 452from a bio-Z signal 450 may be explained in more detail with referenceto FIG. 45. The sharp change 456 in the bio-Z respiratory magnitude dueto OSA is typically in the range of 1 to 4 times the magnitude of thepeak-to-peak respiratory cycle magnitude. The sharp change 456 typicallytakes less than 5 seconds to occur. OSA tends to occur in a recurringsequence where the period (T) between sequential events is between 15and 120 seconds. A one-minute period is commonly observed. According tothese characteristics, OSA events may be detected, identified andflagged for the step of fiducial extraction 378 wherein data (e.g.,event duration, CV, PP range, PPmin, PPmax, etc.) may be time stampedand stored with an event identifier.

The step of extracting 374 waveform data indicative of a CSA event 462from a bio-Z signal 460 may be explained in more detail with referenceto FIG. 46. The behavior of the Bio-Z signal throughout recurrent CSAevents differ from other hypopnea and OSA in three ways. First, duringCSA there is complete cessation of respiratory activity which results ina flat Bio-Z signal. This means the ratio of PPmax to PPmin is typicallygreater than 5 during recurrent CSA events. The duration of theestimated respiratory cycle may also be used to distinguish between CSAfrom OSA and hypopnea. The lack of respiratory activity during CSAresults in an inflated estimate for the respiratory cycle period. The PPtypically does not vary by more than 50% for successive cycles. Therespiratory cycle duration during a CSA event is more than twice as longas the duration of the respiratory cycles preceding the CSA event.Second, during CSA the Bio-Z magnitude will drift outside the PPmagnitude range observed during respiration. It has been observed thatwith the onset of central sleep apnea (CSA) the magnitude and phase ofthe Bio-Z signal settle to a steady-state value outside the peak-to-peakrange observed during the normal respiratory cycle during sleep. Third,upon arousal from CSA a person will typically gasp. This gasp results ina large PP. The PP of the first respiratory cycle following the CSAevent and the PP observed during the CSA (which is essentially noise)will exceed 50% of PPmax.

With continued reference to FIG. 46, the flat portions 468 of the datatraces are periods of respiratory cessation. Upon arousal the subjectgasps 466 and the raw bio-Z signal resumes cyclic oscillation above thestatic impedance level observed during CSA. According to thesecharacteristics, CSA events may be detected, identified and flagged forthe step of fiducial extraction 378 wherein data (e.g., event duration,CV, PP range, PPmin, PPmax, etc.) may be time stamped and stored with anevent identifier.

The step of extracting 374 waveform data indicative of sleep stage(e.g., rapid eye movement (REM) sleep vs. no-rapid eye movement (NREM)sleep) may be performed by comparing the phase difference between afirst vector and a second vector wherein the first bio-Z vector is alongthe lung-diaphragm-liver interface (e.g., vector A-K or vector B-K) andthe second bio-Z vector is about the lung(s). Examples of the firstbio-Z vector include A-K, B-K, A-E1, B-E1, and A-B. Examples of thesecond bio-Z vector include D-F, B-D, C-G, D-E1, and C-E1. Note thatsome vector combinations which share a common vector endpoint such asA-E1, D-E1 and B-E1, B-D may use a common electrode and to simplify therespiratory sensing lead or leads. Typically, during NREM sleep, the twovectors are substantially in phase. During REM sleep, the diaphragm isthe primary respiratory driver and a common consequence is paradoxicalmotion of the ribcage and diaphragm (i.e., the two vectors aresubstantially out of phase). This characteristic would allow for aneffective monitor of a person's ability to reach REM sleep. Accordingly,REM and NREM sleep stages may be detected, identified, and flagged forthe step of fiducial extraction 378 wherein characteristic data (e.g.,event duration, phase, etc.) may be time stamped and stored with anevent identifier.

An alternative method of detecting an OSA event is to make use of asplit current electrode arrangement as shown in FIG. 47 which shows thepositions of three electrodes on the subject. Electrode A may be abovethe zyphoid, electrode B may be just above the belly button, andelectrode C may be on the back a couple of inches below electrode A.Electrodes A and B are connected to a common constant current sourcethrough resistors R1 and R2. The voltage measured across the currentsource is a measure of the bio-impedance during normal respiration. Thevoltage across R1 is an indicator of the paradoxical motion associatedwith apnea. An unbalanced current split between R1 and R2 resulting inlarge bio-Z voltage swings is indicative of OSA. During normalrespiration or even very deep breaths there is almost no effect on theapnea detection channel. Accordingly, OSA events may be detected,identified, and flagged for the step of fiducial extraction 378 whereincharacteristic data (e.g., event duration, voltage swing magnitude,etc.) may be time stamped and stored with an event identifier.

Generally, the extracted 378 waveform and event data may be used fortherapy tracking, for stimulus titration, and/or for closed loop therapycontrol. For example, data indicative of apneas and hypopneas (or otherevents) may be stored by the INS 50 and/or telemetered to the patientcontrolled 40. The data may be subsequently transmitted or downloaded tothe physician programmer 30. The data may be used to determinetherapeutic efficacy (e.g., apnea hypopnea index, amount of REM sleep,etc.) and/or to titrate stimulus parameters using the physicianprogrammer 30. The data may also be used to control stimulus in a closedloop fashion by, for example, increasing stimulus intensity duringperiods of increased apnea and hypopnea occurrence or decreasingstimulus intensity during periods of decreased apnea and hypopneaoccurrence (which may be observed if a muscle conditioning effect isseen with chronic use). Further, the data may be used to turn stimuluson (e.g., when apnea or hypopnea events start occurring or when motionartifact is absent) or to turn stimulus off (e.g., when no apnea orhypopnea events are occurring over a present time period or when motionartifact is predominant).

Description of Stimulus Trigger Algorithms

As mentioned previously with reference to FIG. 39, the neurostimulationsystem described herein may operate in a closed-loop process wherein thestep of delivering stimulation 390 to the targeted nerve may be afunction of a sensed feedback parameter (e.g., respiration). Forexample, stimulation of the hypoglossal nerve may be triggered to occurduring the inspiratory phase of respiration. In a health human subject,the hypoglossal nerve is triggered about 300 mS before inspiration.Accordingly, a predictive algorithm may be used to predict theinspiratory phase and deliver stimulation accordingly. FIG. 48schematically illustrates a system 480 including devices, data andprocesses for implementing a self-adjusting predictive triggeralgorithm.

The system components 482 involved in implementing the algorithm mayinclude the physician programmer (or patient controller), INS andassociated device memory, and the respiratory sensor(s). The sensors anddevice memory are the sources of real-time data and historical fiducialdata which the current algorithm uses to generate a stimulation triggersignal. The data 484 utilized in implementing the algorithm may includepatient specific data derived from a sleep study (i.e., PSG data), datafrom titrating the system post implantation, and historic and real-timerespiratory data including respiratory and event fiducials. Theprocesses 486 utilized in implementing the algorithm may includeproviding a default algorithm pre-programmed in the INS, patientcontroller or physician programmer, modifying the default algorithm, andderiving a current algorithm used to generate a trigger signal 488.

More specifically, the processes 486 utilized in implementing apredictive trigger algorithm may involve several sub-steps. First, adefault algorithm may be provided to predict onset of inspiration fromfiducial data. Selecting an appropriate default algorithm may depend onidentifying the simplest and most robust fiducial data subsets whichallow effective prediction of onset. It also may depend on a reliablemeans of modifying the algorithm for optimal performance. Second,modification of the default algorithm may require a reference datum. Thereference datum may be the estimated onset for past respiratory cycles.It is therefore useful to precisely estimate inspiratory onset forprevious respiratory cycles from historical fiducial data. Thisestimation of inspiratory onset for previous respiratory cycles may bespecific to person, sensor location, sleep stage, sleep position, or avariety of other factors. Third, the current algorithm may be derivedfrom real-time and historical data to yield a stimulation trigger signal488.

As alluded to above, a trigger algorithm, such as, for example, triggeralgorithm 4700 depicted in FIG. 47A, may be applied to a detectedrespiratory signal to begin and/or control delivery of the stimulationsignal. As illustrated, trigger algorithm 4700 may include a pluralityof sub-routines 4701-4703 for performing various analyses on a sensedrespiratory signal. These sub-routines may include, but are not limitedto, performing peak detection 4701, error checking 4702, and prediction4703, on a detected respiratory signal.

With reference now to FIG. 47D, there is depicted an exemplary sensedrespiratory signal 4750. Respiratory signal 4750 may be displayed as asubstantially sinusoidal waveform having a component that varies withtime. As shown in FIG. 47D, respiratory signal 4750 may include aplurality of peaks, such as, for example, the peak located at v₄t₄, anda plurality of valleys, such as, for example, the valley located v⁻ ₄t⁻₄. Therefore, as will be discussed in greater detail below, peakdetection sub-routine 4701 may be applied to sensed respiratory signal4750 to detect the peaks of signal 4750. Error checking sub-routine 4702may be applied to signal 4750 to, among other things, ensure signal 4750is an accurate representation of a patient's respiration and free fromundesirable artifacts caused by, for example, a patient's movement orcardiac activity. Prediction sub-routine 4703 may then be applied tosignal 4750 to predict when future peaks will occur in accordance withthe sensed signal 4750.

With reference to FIG. 47B, peak detection 4701 may include a pluralityof steps 4701 a-g. Step 4701 a may include first detecting the peaks,such as, for example, the peak located at v₄t₄, of signal 4750. Thedetected peaks may be an indication of when onset of expiration occursduring the monitored respiratory cycles. Next, step 4701 b may includeacquiring and/or considering a new voltage V_(k), where V_(k) may be themost recently acquired data point time T_(k) under consideration, wherea number of recently acquired data points may be under consideration.Step 4701 c may determine whether the data points under considerationmeet the criteria to indicate that a minimum (min) peak has beendetected. One example of such a criteria to indicate a minimum peak hasbeen detected is if the oldest data point under consideration, V_(k+m)is less than more recent data points under consideration, (V_(k+m−1) . .. V_(k)), which can be expressed mathematically as V_(k+m)≤min(V_(k+m−1) . . . V_(k)). Another example of such a criteria to indicatea minimum peak has been detected is if the most recent data point underconsideration, V_(k), is greater than all other less-recently acquireddata points under consideration, (V_(k+m) . . . V_(k+1)), which can beexpressed mathematically as V_(k)≥max (V_(k+m−1) . . . V_(k+1)). If thecriteria for detecting a minimum peak is not met, step 4701 b may berepeated to acquire and/or consider a new voltage V_(k). If the criteriahas been met, step 4701 d may declare a minimum peak reference. Next,step 4701 e may again acquire and/or consider a new voltage V_(k).Subsequently, step 4701 f may determine whether the data points underconsideration meet the criteria to indicate a maximum peak has beendetected. One example of such a criteria to indicate a maximum peak hasbeen detected is if the oldest data point under consideration, V_(k+m),is greater than more recent data points under consideration (V_(k+m−1) .. . V_(k)), which can be expressed mathematically as V_(k+m)≤max(V_(k+m−1) . . . V_(k)). Another example of such a criteria to indicatea maximum peak has been detected is if the most recent data point underconsideration, V_(k), is less than all other less-recently acquired datapoints under consideration, (V_(k+m) . . . V_(k+1)), which can beexpressed mathematically as V_(k)≤max (V_(k+m) . . . V_(k+1)). If thecriteria for detecting a maximum peak is not met, step 4701 e may berepeated to acquire and/or consider a new voltage V_(k). If the criteriahas been met, step 4701 g may declare a maximum peak, and triggeralgorithm 4700 may proceed to error-checking sub-routine 4702. Thedeclared peak will depend on the criteria used for peak detection. Forexample, if the criteria for detecting a peak was based on comparingV_(k) to less recently acquired data points, (V_(k+m) . . . V_(k+1)),then the peak magnitude and time would be declared to be V_(k+m/2),t_(k+m/2). As another example, if the criteria for detecting a peak wasbased on comparing the oldest considered data point, V_(k+m), to morerecently acquired data points (V_(k+m) . . . V_(k)), then the peakmagnitude and time would be declared to be V_(k+m), t_(k+m).

With reference now to FIG. 47C, error-checking sub-routine 4702 mayinclude a plurality of steps 4702 a-e to determine whether a sensedrespiratory signal may be adequate for respiration detection. Forexample, step 4702 a, peak correction, may include receiving informationrelating to the peaks detected in step 4701 and corrections, asnecessary. Next, steps 4702 b-e may include analyzing the sensedrespiratory signal to determine whether the signal includes “noise”caused by a patient's movement (4702 b), whether the signal issub-threshold (e.g., has a relatively low amplitude) (4702 c), whetherthe signal is sufficiently stable (4702 d), and whether the inversiondetection is possible with the sensed signal (4702 e). If the sensedsignal passes all of error-checking steps 4702 b-e, trigger algorithm4700 may proceed to prediction sub-routine 4703. However, if the sensedsignal fails any of steps 4702 b-e, the trigger algorithm may terminateand the pulse generator (e.g., INS 50) may either cease stimulation,continue stimulation with continuous pulses of predetermined duration,and/or continue to stimulate at the same or a fraction (e.g., onequarter) of the stimulation rate for the most recently measuredrespiratory cycle, as discussed in greater detail below.

As described above, a peak is declared for a given set of data pointsunder consideration when a peak detection criteria is met. The declaredpeak itself may be used in further algorithm calculations or a moreprecise estimate of peak time and voltage may be calculated. The moreprecise estimates of peak time and voltage are referred to as the peakcorrection. With regard to step 4702 a, peak correction may becalculated as follows:ΔV _(pk,i) =V _(pk,j) −V _(pk,i−1) for −n≤i≤n

V_(pk,0) is defined to be the declared peak for which a correction isbeing calculated. The difference in voltage between successive datapoints is calculated for a given number of data points, n, to eitherside of the declared peak.

${{\Delta\; V_{{pk},{0\;{th}}}} = {\frac{1}{2\; n}{\sum\;\left( {\Delta\; V_{{pk},i}} \right)}}}\;$

The peak in signal ideally occurs when the rate of change of the signalis zero. Taking successive differences in measured voltage is anapproximation to the rate of change of the signal. Linear regression isused on a range of successive differences to estimate the point in timewhen the rate of change is zero. Due to the fact that the data pointsare collected at equal increments of time, calculating the statisticsΔV_(pk,0th), ΔV_(pk,1st) and DEN allows a simple calculation based onlinear regression to estimate the point in time at which the rate ofchange of the signal is zero.

Δ V_(pk, 1 st) = ∑ (i * Δ V_(pk, i))  for   − n ≤ i ≤ nDEN = ∑ (i²)   for − n ≤ i ≤ n${Correction} = {\Delta\;{V_{{pk},{0\;{th}}}\left( \frac{DEN}{\Delta\; V_{{pk},{1{st}}}} \right)}}$

Additionally, an estimated peak time after correction may be determinedas follows:t′ _(pk,0) =t _(pk,0)+Correction

With regards to step 4702 e, a peak curvature estimate for inversiondetection can be obtained from one of the statistics, ΔV_(pk,1st),calculated for peak correction. Maximum peaks are sharper than minimumpeaks and so typically have higher values of ΔV_(pk,1st.) One means ofdetermining if a signal is inverted would be to compare the values ofΔV_(pk,1st) for a series of maximum peaks to a series of minimum peaks.

With renewed reference to FIG. 47A, prediction sub-routine 4703 mayinclude predicting the time between sequentially identified peaks witheither a parametric option or a non-parametric option. The parametricoption makes a prediction of the duration of the next respiratory periodbased on the average duration of recent respiratory cycles and the rateof change of the duration of recent respiratory cycles. The parametricoption also takes advantage of the fact that data points are collectedat equal increments of time which simplifies the linear regressioncalculation. The parametric option may be defined as follows:Δt _(i) =t _(i) −t _(i−1)

Zeroth order estimate of next peak.Δt _(0,0th)=1/h·Σ(Δt _(i)), for 1≤i≤n

where n is the number of past respiration cycles used.

First Order Estimate

${{\Delta\; f_{0,{1\;{st}}}} = {\sum\;\left( {i - {\left( \frac{n + 1}{2} \right)*\;\Delta\; t_{i}}} \right)}},\mspace{14mu}{{{for}\mspace{14mu} 1} \leq i \leq n}$${{{DEN}\; 1} = {\sum\;\left( \left( {i - \left( \frac{n + 1}{2} \right)} \right)^{2} \right)}},\mspace{14mu}{{{for}\mspace{14mu} 1} \leq i \leq n}$

Predicted Interval Length for Current Respiration Cycle

${\Delta\; t_{0,{pred}}} = {{\Delta\; t_{0,{0{th}}}} + {\left( \frac{\Delta\; t_{0,{1\;{st}}}}{{DEN}\; 1} \right) \cdot \left( \frac{n + 1}{2} \right)}}$

Next Predicted Offset att _(0,pred) =t ₁ +Δt _(0,pred)

Begin therapy delivery at:

t_(therapy)=t₁+(1−DC)*Δt_(0,pred′), where DC may be the allowable dutycycle for therapy delivery.

The non-parametric option is very similar to the parametric option inthat it also estimates the duration of the next respiratory period basedon the nominal duration of recent respiratory cycles and the rate ofchange of the duration of recent respiratory periods. The method isexplained in more detail in “Nonparametric Statistic Method” byHollander and Wolfe in sections related to the Theil statistic and theHodges-Lehman, there disclose of which is incorporated herein byreference. The non-parametric prediction method may be defined asfollows:Δt _(i) =t _(i) −t _(i−1)

Zeroth Order EstimateΔt _(0,oth)=1/2median{Δt _(i) +Δt _(j) ,i+∈ ₀ ≤j≤1, . . . ,n}

Where ∈₀ is optimally 0, 1, 2 or 3

First Order Estimate

$S_{ij} = {{{\frac{{\Delta\; t_{j}} - {\Delta\; t_{i}}}{j - i}1} \leq +} \in_{i}{< j \leq n}}$where ∈₁ is optimally 0, 1, 2, or 3Δt _(0,1n)=median{S _(ij),1≤i≤∈ _(i) <j≤n}

Predicted Interval Length for Current Respiration cycle

${\Delta\; t_{0,\;{pred}}} = {{\Delta\; t_{0,{0\;{th}}}} + {\Delta\;{t_{0,{1\;{st}}} \cdot \left( \frac{n + 1}{2} \right)}}}$

Next Predicted Offsett _(0,pred) =t ₁ +Δt _(0,pred)

Begin Therapy Delivery at

t_(therapy)=t₁+(1−DC)*Δt_(0,pred), where DC may be the allowable dutycycle for therapy delivery.

Stimulation may then commence at the calculated t_(therapy).

With reference to FIG. 48, a self adjusting predictive algorithm may beimplemented in the following manner.

The Programmer block illustrates means by which PSG-derived data may beuploaded into the device.

The Sensors and Device Memory block includes the sources of real-timedata and historical fiducial variables which the current algorithm usesto generate a stimulation trigger signal.

The Patient PSG Titration Data block includes conventionalpolysomnographic (PSG) data obtained in a sleep study. A self-adjustingpredictive algorithm utilizes a reference datum to which the algorithmcan be adjusted. Onset may be defined as onset of inspiration asmeasured by airflow or pressure sensor used in a sleep study, forexample. Estimated Onset may be defined as an estimate of Onsetcalculated solely from information available from the device sensors andmemory. To enable the predictive algorithm to be self-adjusting, eitherOnset or Estimated Onset data is used. During actual use, the implanteddevice will typically not have access to Onset as that would requireoutput from an airflow sensor. The device then may rely on an estimateof Onset or Estimated Onset. The calibration of Estimated Onset to Onsetmay be based on PSG data collected during a sleep study. The calibrationmay be unique to a person and/or sleep stage and/or sleep positionand/or respiratory pattern.

The Historical Fiducial Variables block represents the HistoricalFiducial Variables (or data) which have been extracted from the bio-Zwaveform and stored in the device memory. This block assumes that theraw sensor data has been processed and is either clean or has beenflagged for cardiac, movement, apnea or other artifacts. Note thatfiducial data includes fiducials, mathematical combinations of fiducialsor a function of one or more fiducials such as a fuzzy logic decisionmatrix.

The Real-Time Data and Historical Fiducial Variables block incorporatesall the information content of the Historical Fiducial Variables blockand also includes real-time bio-Z data.

The Default Algorithm block represents one or more pre-set triggeralgorithms pre-programmed into the INS or physician programmer. Thedefault algorithm used at a specific point in time while deliveringtherapy may be selected from a library of pre-set algorithms. Theselection of the algorithm can be made automatically by the INS basedon: patient sleep position (position sensor), heart rate (detectablethrough the impedance measuring system) or respiration rate. Clinicalevidence supports that the algorithm used to predict the onset ofinspiration may be dependent on sleep position, sleep state or otherdetectable conditions of the patient.

The Modify Algorithm block represents the process of modifying theDefault Algorithm based on historical data to yield the CurrentAlgorithm. Once the calibration of Estimated Onset to Onset is residentin the device memory it can be used to calculate Estimated Onset forpast respiratory cycles from Fiducial Variables. The variable used torepresent the Estimated Onset will be TEST or TEST(i) where the “i”indicates the cycle number. Note that Estimated Onset is calculated forpast respiratory cycles. This means that sensor fiducial variables whicheither proceed or follow each Onset event may be used to calculate theEstimated Onset.

The Current Algorithm block represents the process of using the ModifiedDefault Algorithm to predict the next inspiratory onset (PredictedOnset). The Predicted Onset for the next respiratory cycle may becalculated from real-time data and historical fiducial variables. Thecalculation may be based on the Modified Default Algorithm. Modificationof the Modified Default Algorithm to derive the Current Algorithm may bedependent on the calibration of Estimated Onset to Onset which was inputfrom the physician programmer and may be based on comparison ofreal-time bio-Z data to data collected during a PSG titration study. TheCurrent Algorithm may use historic and/or real-time sensor fiducialvariables to predict the next onset of inspiration. This predicted onsetof inspiration may be referred to as Predicted Onset. The variable usedto represent Predicted Onset may be TPRED or TPRED(i) where the “i”indicates the respiratory cycle.

The Stimulation Trigger Signal block represents the Current Algorithmgenerating a trigger signal which the device uses to trigger stimulationto the hypoglossal nerve.

FIG. 49 is a table of some (not all) examples of waveform fiducialswhich can be extracted from each respiratory cycle waveform. For eachfiducial there is a magnitude value and a time of occurrence. Eachwaveform has a set of fiducials associated with it. As a result,fiducials may be stored in the device memory for any reasonable numberof past respiratory cycles. The values from past respiratory cycleswhich are stored in device memory are referred to as Historical FiducialVariables.

The graphs illustrated in FIG. 50 are examples of fiducials marked onbio-Z waveforms. The first of the three graphs illustrate thebio-impedance signal after it has been filtered and cleared of cardiacand motion artifacts. The first graph will be referred to as the primarysignal. The second graph is the first derivative of the primary signaland the third graph is the second derivative of the primary signal. Eachgraph also displays a square wave signal which is derived from airflowpressure. The square wave is low during inspiration. The falling edge ofthe square wave is onset of inspiration.

Due to the fact that it may be difficult to identify onset ofinspiration in real-time from respiratory bio-impedance, a goal is toconstruct an algorithm which can reliably predict onset of inspiration“T” for the next respiratory cycle from information available from thecurrent and/or previous cycles. A reliable, distinct and known referencepoint occurring prior to onset of inspiration, “T”, is “A”, the peak ofthe primary signal in the current cycle. As can be seen in FIG. 50, theupper peak of the bio-Z waveform “A” approximately corresponds to theonset of expiration “O.” A dependent variable t_(T-PK) is created torepresent the period of time between the positive peak of the primarysignal for the current cycle, t.Vmax(n), indicated by “A_(n)” on thegraph, and onset of inspiration for the next cycle, t.onset(n+1),indicated by “T” on the graph. The variable t_(T-Pk) may be defined as:t _(r-PK) =t.onset(n+1)−t.V max(n)

Note that t.Vmax could be replaced by any other suitable fiducial indefining a dependent variable for predicting onset.

A general model for a predictive algorithm may be of the following form:t _(T-PK) =f(fiducials extracted from current and/or previous cycles)

A less general model would be to use a function which is a linearcombination of Fiducial Variables and Real-Time Data.

The following fiducials may be both highly statistically significant andpractically significant in estimating T:t.V max(n)=the time where positive peak occurs for the current cycle;t.dV.in(n)=the time of most positive 1st derivative during inspirationfor the current cycle; andt.V max(n−1)=the time of positive peak for the previous cycle.

This model can be further simplified by combining the variables asfollows:Δt.pk(n)=t.V max(n)−t.V max(n−1)Δt.in(n)=t.V max(n)−t.dV.in(n)

Either Δt.pk(n) or Δt.in(n) is a good predictor of Onset.

The following example uses Δt.pk(n). The time from a positive peak untilthe next inspiration onset can be estimated by:T _(pred) =t.V max(n)+k0+k1*Δt.pk(n)

The coefficients k0 and k1 would be constantly modified by optimizingthe following equation for recent historical respiratory cycles againstT_(est):T _(est) =t.V max(n)+k0+k1*Δt.pk(n)

Thus, the predictive trigger time T_(pred) may be determined by addingt_(T-PK) to the time of the most recent peak (PK) of the bio-Z signal,where:t _(T-PK) =k0+k1*Δt.pk(n)

The predictive equation we are proposing is based on the fact that thevery most recent cycle times should be negatively weighted. Regressionanalysis supports this approach and indicates a negative weighting isappropriate for accurate prediction of onset. Thus, predicting onset ismore effective if the most recent historical cycle time is incorporatedinto an algorithm with a negative coefficient.

As noted above, stimulation may be delivered for only a portion of therespiratory cycle, such as, for example, during inspiration.Additionally, it may be desirable to begin stimulation approximately 300milliseconds before the onset of inspiration to more closely mimicnormal activation of upper airway dilator muscles. However, predictingand/or measuring inspiration, in particular, the onset of inspiration,may be relatively challenging. Thus, since the onset of expiration maybe relatively easy to measure and/or predict (as discussed in greaterdetail below) when an adequate measure of respiration is available, itis contemplated that stimulation may be triggered as a function ofexpiration onset.

Turning now to FIG. 50A, there is depicted an exemplary respiratorywaveform 5500 for two complete respiratory cycles A and B. In analyzingexemplary waveform 5500, it may be determined that peaks M of thewaveform 5500 may indicate onset of the expiratory phases of respirationcycles A and B. Furthermore, it may be discovered that peaks M occur atregular intervals of approximately 3-4 seconds. Thus, it may berelatively easy to predict the occurrence of subsequent peaks M, andconsequently, the onset of expiration for future respiratory cycles.

Therefore, in order to deliver a stimulus to a patient in accordancewith the principles of the present disclosure, the start of stimulationmay be calculated by first predicting the time intervals between thestart of expiration for subsequently occurring respiratory cycles. Next,in order to capture the entire inspiratory phase, including the briefpre-inspiratory phase of approximately 300 milliseconds, stimulation maybe started at the time N that is prior to the next onset of expirationby approximately 30% to 50% of the time between subsequently occurringexpiratory phases. Stimulating less than 30% or more than 50% prior tothe next expiratory phase may result in an inadequate stimulation periodand muscle fatigue, respectively.

In some embodiments, however, it is contemplated that an adequatemeasure of respiration may not be available, such as, for example, whena relied upon signal has failed. In these embodiments, it iscontemplated that the implanted neurostimulator system may be configuredto respond in one or more of the following three ways. First, theimplanted neurostimulator may completely cease stimulation until anadequate signal is acquired. Second, the neurostimulator may delivercontinuous simulation pulses of predetermined durations (e.g., up to 60seconds) until an adequate signal is acquired; or if an adequate signalis not acquired in this time, the stimulation will be turned off. Third,the neurostimulator may continue to stimulate at the same or a fraction(e.g., one quarter) of the stimulation rate for the most recentlymeasured respiratory cycle. That is to say, the neurostimulator maydeliver stimulation pulses of relatively long durations at a frequencythat is less than the frequency of stimulation utilized with an adequatemeasure of respiration. Alternatively, the neurostimulator may deliverstimulation pulses of relatively short durations at a frequency that isgreater than the frequency used with an adequate measure of respiration.

Respiratory Waveform Analysis Techniques

Referring to FIG. 50A, features of the respiratory waveform, such as thewaveform 5500 characterized with an impedance value, can be identifiedand analyzed to determine patient status, sleep-related events, andresponsiveness to therapy, and can be used to adjust therapy parameters.

In an exemplary embodiment, individual waveforms can be identifiedwithin the respiratory waveform 5500 and further analyzed to identifypatient status and the occurrence of obstructive sleep apnea events. Anindividual waveform can be defined to be a portion of the respiratorywaveform extending between two sequential impedance peaks or between twoother similar waveform features. The amplitude of the impedance peaks,or the peaks of a waveform measured by another means, can be compared toa threshold to determine the level of effort required for a respirationcycle. A high or otherwise significant level of effort in therespiratory effort of an individual respiratory waveform can identifydisordered or atypical breathing indicative of an obstructive sleepapnea event. As can be appreciated, the measurement technique used toacquire the respiratory waveform, and the selection of the threshold,would require calibration based on a baseline related to the normal orusual respiratory effort for the patient, and to account for theconfiguration of the sensors measuring respiratory effort.

In another exemplary embodiment, the inspiratory stage of a restrictedbreath can be analyzed to determine whether it provides a value thatexceeds the value associated with a normal breath. The inspiratory stagecan be defined to be a portion of the respiratory waveform, such asrespiratory waveform 5500, that relates to the intake or the attemptedintake of air into the lungs. One method of measuring the inspiratorystage can be to measure the period between the impedance peak of theinspiration and the preceding impedance negative peak to represent theinspiratory period of breath. By isolating and analyzing the inspiratorystage of the respiratory waveform, and by analyzing the effort requiredover the period of time correlated to the inspiratory stage, the amountof effort over time can be determined for an entire inspiration andprovided as a value that can be compared to a threshold. In an exemplaryuse of a threshold, a measured inspiratory period of breath can beidentified and compared to the entire duration of the respiratory periodand, for example, a disordered breath can be identified when it isdetermined that the inspiratory period of breath is at least 40% of theentire respiratory period. As can be appreciated, the technique can beapplied to only a portion of the inspiratory stage, such as an initialportion of the inspiration stage, to provide a value for the effort orenergy required to initial the inspiration, and a value can be providedrepresenting initial inspiration effort that can be compared to athreshold.

Description of an Exemplary Stimulation Pulse

Turning now to FIG. 50B, there is depicted an exemplary stimulationpulse waveform 5000 that may be emitted from an INS in accordance withthe principles of the present disclosure. Typically, exemplarystimulation pulse waveform 5000 may include a square wave pulse trainhaving one or more square wave pulses 5001 of approximately 1 to 3 voltsin amplitude, a duration of approximately 100 ms, and a frequency ofapproximately 30 Hz, assuming a 1000 ohm impedance at the electrodes anda constant current or voltage.

In some embodiments, exemplary stimulation pulse waveform 5000 mayinclude a bi-phasic charge balanced waveform square pulses 5001 and5002, as depicted in FIG. 50B. Square pulse 5002 may be included inwaveform 5000 to, among other things, promote efficient stimulationand/or mitigate electrode corrosion. However, square pulse 5002 may beexcluded from waveform 5000 as desired. Furthermore, although thedepicted exemplary waveform 5000 includes square pulse 5002 that exactlybalances the stimulation wave pulse 5001, in certain circumstances,square pulse 5002 may not exactly balance the stimulation wave pulse5001, and may not be a square pulse.

In some embodiments, exemplary stimulation pulse waveform 5000 mayinclude the delivery of a low amplitude (e.g., below the stimulationthreshold), long duration, pre-stimulation pulse 5004. Thepre-stimulation pulse 5004 may include any suitable low amplitude, longduration pulse, and may be provided approximately 0.5 ms before thedelivery of a first stimulation pulse 5001.

Pre-stimulation pulse 5004 may facilitate selectively stimulatingcertain fibers of a nerve, such as, for example, the hypoglossal nerveor the superior laryngeal nerve. In particular, when stimulating thehypoglossal nerve, the presence of a pre-stimulation pulse, such as, forexample, pulse 5004, before a stimulation pulse (e.g., the bi-phasicstimulation pulse 5001 depicted in FIG. 50B) may serve to saturate thelarge diameter fibers of the nerve so as to allow the stimulation pulse5001 to only affect (e.g., stimulate) the smaller diameter fibers of thenerve. In circumstances where a nerve (e.g., the hypoglossal nerve) maybe stimulated for extended periods of time, a pre-stimulation pulse 5004may be selectively introduced to waveform 5000, so as to permitselective switching between stimulating the large and small diameterfibers of the nerve, in order to reduce muscle fatigue. Similarly, insituations where OSA may be treated by stimulating the superiorlaryngeal nerve to open the upper airway through a reflex mechanism, thepresence of pre-stimulation pulse 5004 may serve to saturate the largerdiameter efferent fibers so as to allow the stimulation pulse 5001 toonly affect the smaller diameter afferent fibers of the nerve.

Description of External (Partially Implanted) System

With reference to FIGS. 51A and 51B, an example of an externalneurostimulator system inductively coupled to an internal/implantedreceiver is shown schematically. The system includes internal/implantedcomponents comprising a receiver coil 910, a stimulator lead 60(including lead body 62, proximal connector and distal nerve electrode64). Any of the stimulation lead designs and external sensor designsdescribed in more detail herein may be employed in this genericallyillustrated system, with modifications to position, orientation,arrangement, integration, etc. made as dictated by the particularembodiment employed. The system also includes external componentscomprising a transmit coil 912 (inductively linked to receiver coil 910when in use), an external neurostimulator or external pulse generator920 (ENS or EPG), and one or more external respiratory sensors 916/918.

As illustrated, the receiver coil 910 is implanted in a subcutaneouspocket in the pectoral region and the stimulation lead body 62 istunneled subcutaneously along the platysma in the neck region. The nerveelectrode 64 is attached to the hypoglossal nerve in the submandibularregion.

The transmitter coil 912 may be held in close proximity to the receivercoil 910 by any suitable means such as an adhesive patch, a belt orstrap, or an article of clothing (e.g., shirt, vest, brazier, etc.)donned by the patient. For purposes of illustration, the transmittercoil 912 is shown carried by a t-shirt 915, which also serves to carrythe ENS 920 and respiratory sensor(s) 916, 918. The ENS 920 may bepositioned adjacent the waist or abdomen away from the ribs to avoiddiscomfort while sleeping. The respiratory sensor(s) 916, 918 may bepositioned as a function of the parameter being measured, and in thisembodiment, the sensors are positioned to measure abdominal andthoracic/chest expansion which are indicative of respiratory effort, asurrogate measure for respiration. The external components may beinterconnected by cables 914 carried by the shirt or by wireless means.The shirt may incorporate recloseable pockets for the externalcomponents and the components may be disconnected from the cables suchthat the reusable components may be removed from the garment which maybe disposed or washed.

The transmitting coil antenna 912 and the receiving coil antenna 910 maycomprise air core wire coils with matched wind diameters, number of wireturns and wire gauge. The wire coils may be disposed in a disc-shapedhermetic enclosure comprising a material that does not attenuate theinductive link, such as a polymeric or ceramic material. Thetransmitting coil 912 and the receiving coil 910 may be arranged in aco-axial and parallel fashion for coupling efficiency, but are shownside-by-side for sake of illustration only.

Because power is supplied to the internal components via an inductivelink, the internal components may be chronically implanted without theneed for replacement of an implanted battery, which would otherwiserequire re-operation. Examples of inductively powered implantablestimulators are described in U.S. Pat. No. 6,609,031 to Law et al., U.S.Pat. No. 4,612,934 to Borkan, and U.S. Pat. No. 3,893,463 to Williams,the entire disclosures of which are incorporated herein by reference.

With reference to FIGS. 51C-51G, alternative embodiments of an externalneurostimulator system inductively coupled to an internal/implantedreceiver are schematically shown. These embodiments are similar to theexternal embodiment described above, with a few exceptions. In theseembodiments, the receiver coil 910 is implanted in a positionedproximate the implanted stimulation lead body 62 and nerve electrode 64.The receiver coil 910 may be positioned in a subcutaneous pocket on theplatysma muscle under the mandible, with the lead body 62 tunneling ashort distance to the nerve electrode 64 attached to the hypoglossalnerve. Also in these embodiments, the respiratory sensor(s) 916/918 maybe integrated into the ENS 920 and attached to a conventionalrespiratory belt 922 to measure respiratory effort about the abdomenand/or chest. An external cable 914 connects the ENS 920 to thetransmitter coil 912.

In the embodiment of FIG. 51D, the transmitter coil 912 is carried by anadhesive patch 924 that may be placed on the skin adjacent the receivercoil 910 under the mandible. In the embodiment of FIG. 51E, thetransmitter coil 912 is carried by an under-chin strap 926 worn by thepatient to maintain the position of the transmitter coil 912 adjacentthe receiver coil 910 under the mandible. In the embodiment of FIG. 51F,the receiver coil 910 may be positioned in a subcutaneous pocket on theplatysma muscle in the neck, with the lead body 122 tunneling a slightlygreater distance. The transmitter coil 912 may be carried by a neckstrap 928 worn by the patient to maintain the position of thetransmitter coil 912 adjacent the receiver coil 910 in the neck.

With reference to FIGS. 51G-51K, additional alternative embodiments ofan external neurostimulator system inductively coupled to aninternal/implanted receiver are schematically shown. These embodimentsare similar to the external embodiment described above, with a fewexceptions. As above, the receiver coil 910 may be positioned in asubcutaneous pocket on the platysma muscle under the mandible, with thelead body 62 tunneling a short distance to the nerve electrode 64attached to the hypoglossal nerve. However, in these embodiments, theENS 920 (not shown) may be located remote from the patient such as onthe night stand or headboard adjacent the bed. The ENS 920 may beconnected via a cable 930 to a large transmitter coil 912 that isinductively coupled to the receiver coil 910. The respiratory sensor 916may comprise a conventional respiratory belt 922 sensor to measurerespiratory effort about the abdomen and/or chest, and sensor signalsmay be wirelessly transmitted to the remote ENS 920. As compared toother embodiments described above, the transmitter coil 912 is notcarried by the patient, but rather resides in a proximate carrier suchas a bed pillow, under a mattress, on a headboard, or in a neck pillow,for example. Because the transmitter coil 912 is not as proximate thereceiver coil as in the embodiments described above, the transmittercoil may be driven by a high powered oscillator capable of generatinglarge electromagnetic fields.

As shown in FIG. 51H, the transmitter coil 912 may be disposed in a bedpillow 934. As shown in FIG. 51I, the transmitter coil 912 may comprisea series of overlapping coils disposed in a bed pillow 934 that aresimultaneously driven or selectively driven to maximize energy transferefficiency as a function of changes in body position of the patientcorresponding to changes in position of the receiver coil 910. Thisoverlapping transmitter coil arrangement may also be applied to otherembodiments such as those described previously wherein the transmittercoil is carried by an article donned by the patient. In FIG. 51J, two ormore transmitter coils 912 are carried by orthogonal plates 936 arrangedas shown to create orthogonal electromagnetic fields, thereby increasingenergy transfer efficiency to compensate for movement of the patientcorresponding to changes in position of the receiver coil 910. FIG. 51Jalso illustrates a non-contact respiratory sensor 916 arrangement asutilized for detecting sudden infant death syndrome (SIDS). As shown inFIG. 51K, two orthogonal transmitter coils 912 are located on each sideof a neck pillow 938, which is particularly beneficial for bilateralstimulation wherein a receiver coil 910 may be located on either side ofthe neck.

With reference to FIG. 51L (front view) and 51M (rear view), externalrespiratory effort sensors 916/918 are schematically shown incorporatedinto a stretchable garment 945 donned by the patient. The sensors916/918 generally include one or more inductive transducers and anelectronics module 942. The inductive transducers may comprise one ormore shaped (e.g., zig-zag or sinusoidal) stranded wires to accommodatestretching and may be carried by (e.g., sewn into) the garment 945 toextend around the patient's abdomen and chest, for example. As thepatient breathes, the patient's chest and/or abdomen expands andcontracts, thus changing the cross-sectional area of the shape (i.e.,hoop) formed by the wire resulting in changes in inductance. Theelectronics module may include an oscillator (LC) circuit with theinductive transducer (L) comprising a part of the circuit. Changes infrequency of the oscillator correspond to changes in inductance of theshaped wires which correlate to respiratory effort. The electronicsmodule may be integrated with an ENS (not shown) or connected to an ENSvia a wired or wireless link for triggering stimulus as describedpreviously.

The garment 945 may include features to minimize movement artifact andaccommodate various body shapes. For example, the garment 945 may beform-fitting and may be sleeveless (e.g., vest) to reduce sensorartifacts due to arm movement. Further, the garment 945 may be tailoredto fit over the patient's hips with a bottom elastic band which helpspull the garment down and keep the sensors 916/918 in the properlocation.

Description of a Specific External (Partially Implanted) Embodiment

With reference to FIGS. 52A-52H a specific embodiment utilizing anexternal neurostimulator system inductively coupled to aninternal/implanted receiver is schematically shown. With initialreference to FIG. 52A, the illustrated hypoglossal nerve stimulatorincludes several major components, namely: an implantable electronicsunit that derives power from an external power source; a stimulationdelivery lead that is anchored to the nerve or adjacent to the nerve andprovides electrical connection between the electronics unit and thenerve, an external (non-implanted) power transmitting device that isinductively coupled with the implant to convey a powering signal andcontrol signals; a power source for the external device that is eithersmall and integrated into the body-worn coil and transmitter or is wiredto the transmitter and transmit induction coil and can be powered byprimary or secondary batteries or can be line powered; and a respiratorysensor such as those described previously.

These components may be configured to provide immediate or delayedactivation of respiration controlled stimulation. Initiation of thestimulation regimen may be by means of activation of an input switch.Visual confirmation can be by an LED that shows adequate signal couplingand that the system is operating and is or will be applying stimulation.As a means of controlling gentleness of stimulation onset and removal,either pulse width ramping of a constant amplitude stimulation signalcan be commanded or amplitude of a constant pulse width stimulationsignal or a combination thereof can be performed.

The electrical stimulation signal is delivered by the stimulation leadthat is connected to the implanted nerve stimulator and attached to orin proximity of a nerve. The implanted electronics unit receives powerthrough a magnetically coupled inductive link. The operating carrierfrequency may be high enough to ensure that several cycles (at least 10)of the carrier comprise the output pulse. The operating frequency may bein a band of frequencies approved by governmental agencies for use withmedical instruments operating at high transmitted radio frequency (RF)power (at least 100 milliwatts). For example, the operating frequencymay be 1.8 MHz, but 13.56 MHz is also a good candidate since it is inthe ISM (Industrial/Scientific/Medical) band. The non-implanted(external) transmitter device integrates respiration interface, waveformgeneration logic and transmit power driver to drive an induction coil.The power driver generates an oscillating signal that drives thetransmitter induction coil and is designed to directly drive a coil ofcoil reactance that is high enough or can be resonated in combinationwith a capacitor. Power can come from a high internal voltage that isused to directly drive the transmit induction coil or power can comefrom a low voltage source applied to a tap point on the induction coil.

With reference to FIGS. 52B-52E and 52H, the waveform generation logicmay be used to modulate the carrier in such a way that narrow gaps inthe carrier correspond to narrow stimulation pulses. When stimulatorpulses are not needed, interruptions to the carrier are stopped but thecarrier is maintained to ensure that power is immediately availablewithin the stimulator upon demand. Presence or absence of electricalnerve stimulation is based on respiration or surrogates thereof. Thetransmitted signal may comprise a carrier of about 1.8 MHz. To controlthe implanted electronics unit to generate individual nerve stimulationpulses, the carrier signal is interrupted. The duration of theinterruption is about equal to the duration of the output stimulationpulse. The stimulation pulses may be about 110 microseconds in durationand are repeated at a rate of approximately 33 per second. In addition,multiple pulses can be transmitted to logic within the implant tocontrol stimulation pulse amplitude, pulse width, polarity, frequencyand structure if needed. Further, onset and removal of stimulation canbe graded to manage patient discomfort from abruptness. Grading maycomprise pulse width control, signal amplitude control or a combinationthereof.

An indicator (not shown) may be used to show when the transmitter isproperly positioned over the implant. The indicator may be a part of thetransmitter or by way of communication with the transmitter, or a partof related patient viewable equipment. Determination of proper positionmay be accomplished by monitoring the transmitter power output loadingrelative to the unloaded power level. Alternatively, the implant receivesignal level transmitted back by a transmitter within the implant may bemonitored to determine proper positioning. Or, the implant receivesignal level that is communicated back to the transmitter by momentarilychanging the loading properties presented to the transmitter, such ashorting out the receive coil may be monitored to determine properpositioning. Such communication may be by means of modulation such aspulse presence, pulse width, pulse-to-pulse interval, multi-pulsecoding.

The transmitter may be powered by an internal primary power source thatis used until it is exhausted, a rechargeable power source or a powersource wired to a base unit. In the case of the wired base unit, powercan be supplied by any combination of battery or line power.

The respiration interface may transduce sensed respiratory activity toan on-off control signal for the transmitter. Onset of stimulation maybe approximately correlated slightly in advance of inspiration and laststhrough the end of inspiration, or onset may be based on anticipation ofthe next respiration cycle from the prior respiration cycle or cycles.The respiration sensor may comprise any one or combination of devicescapable of detecting inspiration. The following are examples: one ormore chest straps; an impedance sensor; an electromiographicalmeasurement of the muscles involved with respiration; a microphone thatis worn or is in proximity to the patients' face; a flow sensor; apressure sensor in combination with a mask to measure flow; and atemperature sensor to detect the difference between cool inspired airversus warmed expired air.

The circuit illustrated in FIG. 52F may be used for the implantedelectronics unit. There are five main subsystems within the design: areceive coil, a power rectifier, a signal rectifier, an output switchand an output regulator. The signal from the inductive link is receivedby L1 which is resonated in combination with C1 and is delivered to boththe power and signal rectifiers. Good coupling consistent with lowtransmitter coil drive occurs when the transmit coil diameter is equalto the receive coil diameter. When coil sizes are matched, couplingdegrades quickly when the coil separation is about one coil diameter. Alarge transmit coil diameter will reduce the criticality of small coilspacing and coil-to-coil coaxial alignment for maximum signal transferat the cost of requiring more input drive power.

The power rectifier may comprise a voltage doubler design to takemaximum advantage of lower signal levels when the transmit to receivecoil spacing is large. The voltage doubler operates with an input ACvoltage that swing negative (below ground potential) causes D1 toconduct and forces C2 to the maximum negative peak potential (minus adiode drop). As the input AC voltage swings away from maximum negative,the node of C2, D1, D2 moves from a diode drop below ground to a diodedrop above ground, forward biasing diode D2. Further upswing of theinput AC voltage causes charge accumulated on C2 to be transferredthrough D2 to C3 and to “pump up” the voltage on C3 on successive ACvoltage cycles. To limit the voltage developed across C3 so that anover-voltage condition will not cause damage, and Zener diode, D3 shuntsC3. Voltage limiting imposed by D3 also limits the output of the signalrectifier section. The power rectifier has a long time constant,compared to the signal rectifier section, of about 10 milliseconds.

The signal rectifier section may be similar in topology to the powerrectifier except that time constants are much shorter—on the order of 10microseconds—to respond with good fidelity to drop-outs in thetransmitted signal. There is an output load of 100K (R1) that imposes acontrolled discharge time constant. Output of the signal rectifier isused to switch Q1, in the output switching section, on and off.

The output switching section compares the potential of C3 to that acrossC5 by means of the Q1, Q2 combination. When there is a gap in thetransmitted signal, the voltage across C5 falls very rapidly incomparison with C3. When the voltage difference between C5 and C3 isabout 1.4 volts, Q1 and Q2 turn on. Q1 and Q2 in combination form a highgain amplifier stage that provides for rapid output switching time. R3is intended to limit the drive current supplied to Q2, and R2 aids indischarging the base of Q2 to improve the turn-off time.

In the output regulator section, the available power rectifier voltageis usually limited by Zener diode D3. When the coil separation becomessuboptimal or too large the power rectifier output voltage will be comevariable as will the switched voltage available at the collector of Q2.For proper nerve stimulation, it may be necessary to regulate the(either) high or variable available voltage to an appropriate level. Anacceptable level is about 3 volts peak. A switched voltage is applied toZener diode D6 through emitter follower Q3 and bias resistor R5. Whenthe switched voltage rises to a level where D6 conducts and developsabout 0.6 volts across R4 and the base-emitter junction of Q4, Q4conducts. o Increased conduction of Q4 is used to remove bias from Q3through negative feedback. Since the level of conduction of Q4 is a verysensitive function of base to emitter voltage, Q4 provides substantialamplification of small variations in D6 current flow and therefore biasvoltage level. The overall result is to regulate the bias voltageapplied to Zener diode D6. Output is taken from the junction of theemitter of Q3 and D6 since that point is well regulated by thecombination of Zener diode breakdown voltage combined with theamplification provided by Q4. In addition to good voltage regulation athe junction of the emitter of Q3 and D6, the output is very tolerant ofload current demand since the conductivity of Q3 will be changed byshifts in the operating point of Q4. Due to amplification by Q3 and Q4,the circuit can drive a range of load resistances. Tolerable loadresistances above 1000 ohms and less than 200 ohms. The regulator hasthe advantage of delivering only the current needed to operate the loadwhile consuming only moderate bias current. Further, bias current isonly drawn during delivery of the stimulation pulse which drops to zerowhen no stimulation is delivered. As a comparison, a simple seriesresistance biased Zener diode requires enough excess current to delivera stimulation pulse and still maintain adequate Zener bias. As a furthercomparison, conventional integrated circuit regulators, such as threeterminal regulators are not designed to well regulate and respondquickly to short input pulses. Experiment shows that three-terminalregulators exhibit significant output overshoot and ramp-up time uponapplication of an input pulse. This can be addressed by applying aconstant bias to a regulator circuit or even moving the regulator beforethe output switching stage but this will be at the cost of constantcurrent drain and subsequently reduced range.

The implanted electronics unit may be used to manage the loss of controland power signals. With this design, more than enough stimulation poweris stored in C3 to supply multiple delivered stimulation pulses. Thisdesign is intended to ensure that the voltage drop is minimal on anyindividual pulse. One of the consequences is that when signal is lost,the circuit treats the condition as a commanded delivery of stimulationand will apply a single, extended duration, energy pulse until the fullstored capacity of C3 is empty. An alternative method may be to use anindirect control modulation to command delivery of a nerve stimulationpulse through logic and provide for a time-out that limits pulseduration.

To stimulate tissue, a modified output stage may be used to mitigateelectrode corrosion and establish balanced charging. The output stage isillustrated in FIG. 52G and includes a capacitive coupling between theground side of the stimulator and tissue interface in addition to ashunt from the active electrode to circuit ground for re-zeroing theoutput coupling capacitor when an output pulse is not being activelydelivered.

Description of Alternative Screening Methods

Screening generally refers to selecting patients that will be responsiveto the therapy, namely neurostimulation of the upper airway dilatornerves and/or muscles such as the hypoglossal nerve that innervates thegenioglossus. Screening may be based on a number of different factorsincluding level of obstruction and critical collapse pressure (Pcrit) ofthe upper airway, for example. Because stimulation of the hypoglossalnerve affects the genioglossus (base of tongue) as well as othermuscles, OSA patients with obstruction at the level of the tongue baseand OSA patients with obstruction at the level of the palate and tonguebase (collectively patients with tongue base involvement) may beselected. Because stimulation of the hypoglossal nerve affects upperairway collapsibility, OSA patients with airways that have a lowcritical collapse pressure (e.g., Pcrit of less than about 5 cm water)may be selected. Pcrit may be measured using pressure transducers in theupper airway and measuring the pressure just prior to an apnea event(airway collapse). Alternatively, a surrogate for Pcrit such as CPAPpressure may be used. In this alternative, the lowest CPAP pressure atwhich apnea events are mitigated may correlate to Pcrit.

The critical collapse pressure (Pcrit) may be defined as the pressure atwhich the upper airway collapses and limits flow to a maximal level.Thus, Pcrit is a measure of airway collapsibility and depends on thestability of the walls defining the upper airway as well as thesurrounding pressure. Pcrit may be more accurately defined as thepressure inside the upper airway at the onset of flow limitation whenthe upper airway collapses. Pcrit may be expressed as:Pcrit=Pin−Pout

where

-   -   Pin=pressure inside the upper airway at the moment of airway        collapse; and    -   Pout=pressure outside the upper airway (e.g., atmospheric        pressure).

Other screening methods and tools may be employed as well. For example,screening may be accomplished through acute testing of tongue protrudermuscle contraction using percutaneous fine wire electrodes inserted intothe genioglossus muscle, delivering stimulus and measuring one or moreof several variables including the amount of change in critical openingpressure, the amount of change in airway caliber, the displacement ofthe tongue base, and/or the retraction force of the tongue (as measuredwith a displacement and/or force gauge). For example, a device similarto a CPAP machine can be used to seal against the face (mask) andcontrol inlet pressure down to where the tongue and upper airwaycollapse and occlude during inspiration. This measurement can berepeated while the patient is receiving stimulation of the geneoglossusmuscle (or other muscles involved with the patency of the upper airway).Patients may be indicated for the stimulation therapy if the differencein critical pressure (stimulated vs. non-stimulated) is above athreshold level.

Similarly, a flexible optical scope may be used to observe the upperairway, having been inserted through the mask and nasal passage. Thedifference in upper airway caliber between stimulation andnon-stimulation may be used as an inclusion criterion for the therapy.The measurement may be taken with the inlet air pressure to the patientestablished at a pre-determined level below atmospheric pressure tobetter assess the effectiveness of the stimulation therapy.

Another screening technique involves assessing the protrusion force ofthe tongue upon anterior displacement or movement of the tongue with andwithout stimulation while the patient is supine and (possibly) sedatedor asleep. A minimum increase in protrusion force while understimulation may be a basis for patient selection.

For example, with reference to FIG. 53, a non-invasive oral appliance530 may be worn by the patient during a sleep study that can directlymeasure the protrusion force of the tongue as a basis for patientselection. The oral appliance 530 may include a displacement probe 532for measuring tongue movement protrusion force by deflection (D). Theoral appliance 530 may also include a force sensor 534 for measuring theforce (F) applied by protrusion of the tongue. The sensors in thedisplacement probe 532 and the force sensor 534 may be connected tomeasurement apparatus by wires 536.

FIG. 54 illustrates another example of a non-invasive oral appliance 540that may be worn by the patient during a sleep study to directly measurethe protrusion force of the tongue as a basis for patient selection. Theoral appliance 540 includes a displacement sensor 542 for measuringtongue movement and a force sensor for measuring tongue protrusionforce. The displacement sensor and the force sensor may be connected tomeasurement apparatus by wires 546.

Oral appliances 530 and 540 could be worn during a sleep study and wouldmeasure the tongue protrusion force during (and just prior to) an apneaevent when the protruder muscle tone is presumed to be inadequate tomaintain upper airway patency. The protrusion force measured as theapnea is resolved by the patient will increase as the patient changessleep state and the airway again becomes patent. The force differencemay be used as a basis for patient selection.

Another screening technique involves the use of an oral appliance withsub-lingual surface electrodes contacting the base of the tongue or finewire electrodes inserted into the genioglossus muscle to stimulate thetongue protruder muscle(s) synchronous with respiration during a sleepstudy. The oral appliance may be fitted with a drug delivery system(e.g., drug eluting coating, elastomeric pump, electronically controlledpump) for topical anesthesia to relieve the discomfort of theelectrodes.

For example, with reference to FIG. 55, an oral appliance 550 includes apair of small needle intramuscular electrodes 552 that extend into thegenioglossus. The electrodes 552 are carried by flexible wires 554 andmay be coupled to an external pulse generator (not shown) by wires 556.The electrodes 552 may be supported by a drug (e.g., anesthetic) elutingpolymeric member 558.

Alternatively, with reference to FIG. 56, an oral appliance 560 includesa cathode electrode 562 guarded by two anode electrodes 564 carried by asoft extension 565 that extends under the tongue. The surface electrodes562 and 564 contact the floor of the mouth under the tongue toindirectly stimulate the genioglossus. The electrodes 562 and 564 may becoupled to an external pulse generator (not shown) by wires 566. Theextension 565 may incorporate holes 568 through which a drug (e.g.,anesthetic) may be eluted.

Oral appliances 550 and 560 may be used during a sleep study andstimulation of the target tissue can be performed synchronous withrespiration and while inlet airflow pressure can be modulated. Theability to prevent apneas/hypopneas can be directly determined. Also thecritical opening pressure with and without stimulation can bedetermined. Alternatively or in addition, the intramuscular or surfaceelectrodes may be used to measure genioglossus EMG activity, either withor without stimulation. On any of theses bases, patient selection may bemade.

Patient selection may also be applied to the respiratory sensors todetermine if the respiratory sensors will adequately detect respirationfor triggering stimulation. For example, in the embodiment wherein bio-Zis used to detect respiration using an implanted lead 70, skin surfaceor shallow needle electrodes may be used prior to implantation todetermine if the signal will be adequate. This method may also be suedto determine the preferred position of the electrodes (i.e., optimalbio-Z vector). This may be done while the patient is sleeping (i.e.,during a sleep study) or while the patient is awake.

Description of Alternative Intra-operative Tools

Intra-operatively, it may be desirable to determine the correct portionof the nerve to stimulate in order to activate the correct muscle(s) andimplant the nerve cuff electrode accordingly. Determining the correctposition may involve stimulating at different locations along the lengthor circumference of the nerve and observing the effect (e.g., tongueprotrusion). In addition or in the alternative, and particularly in thecase of field steering where multiple combinations of electrode contactsare possible, it may be desirable to determine optimal electrode orfiled shape combinations.

An example of an intra-operative stimulating tool 570 is shown in FIGS.57A and 57B. In this embodiment, the tool 570 includes a first shaft 571with a distal half-cuff 573. Tool 570 further includes a second shaft575 with a proximal movable collar 574 and a distal half-cuff 575.Stimulating tool 570 includes multiple electrodes 572 on half-cuff 573and/or half-cuff 575 that may be arranged in an array or matrix as shownin FIG. 57C, which is a view taken along line A-A in FIG. 57B. Thehalf-cuffs 573 and 575 may be longitudinally separated for placementabout a nerve and subsequently closed such that the half-cuffs 573 and575 gently grasp the nerve. The electrodes 575 may be sequenced througha series of electrode/field shape combinations to optimize (lower) thecritical opening pressure, airway caliber, tongue protrusion force orother acute indicia of therapeutic efficacy.

The tool 570 may be part of an intra-operative system including: (1)tool 570 or other tool with one or more stimulating electrodes that aredesigned to be easily handled by the surgeon during implant surgery; (2)an external pulse generator which triggers off of a respiration signal;(3) a feedback diagnostic device that can measure critical closingpressure intra-operatively; and (4) an algorithm (e.g., firmware orsoftware in the programmer) that is design to automatically or manuallysequence through a series of electrode configurations that will identifythe best placement of electrode cuffs on the nerves and configuration ofelectrode polarity and amplitude settings. Information from theintra-operative system may greatly speed the process of identifyingwhere to place the electrode cuff(s) on the hypoglossal nerve and whatfield steering may be optimal or necessary to provide efficacy.

In certain circumstances, such as, when treating a child or a smalladult, it may be difficult to implant a nerve cuff electrode of thepresent disclosure about a nerve in a patient's body. Accordingly, itmay be desirable to provide a tool capable of facilitating temporaryexpansion of a nerve cuff electrode of the present disclosure, so as toslip the nerve cuff electrode around a patient's nerve. Turning now toFIGS. 58A-58B, there is depicted a tool 5800 for temporarily expanding anerve cuff electrode in accordance with the principles of the presentdisclosure. Tool 5800 may include a substantially scissor-likeconfiguration having a first element 5801 and a second element 5802pivotably secured together by a suitable fastener, such as, for example,pivot pin 5803, acting as a fulcrum. Elements 5801 and 5802 may besubstantially similar to each other or may differ as necessary. In thedepicted embodiment, elements 5801 and 5802 may include levers havingdistal effecting portions 5804, 5805 and proximal actuating portions5806, 5807.

Proximal actuating portions 5806, 5807 may be of any suitable length andmay be connected to respective handles (not shown), which may be used tooperate tool 5800. Alternatively, proximal actuating portions 5806, 5807themselves may be used to operate tool 5800. Distal effecting portions5804, 5805 may include any suitable configuration to achieve the desiredeffect. For example, each portion 5804, 5805 may include a substantiallycurved configuration. Additionally, a distal end of each portion 5804,5805 may be provided with a fastening mechanism, such as, for example,hook-like projection 5804 a, 5805 a, for facilitating connection of tool5800 to a nerve cuff electrode. As shown in FIGS. 58A-58B, hook-likeprojections 5804 a, 5805 a may be configured to be disposed in differingparallel planes, such that projections 5804 a, 5805 a may be spaced(offset) horizontally from one another. In use, distal effectingportions 5804, 5805 may be opened and closed as proximal actuatingportions 5806, 5807 may be rotated about pivot pin 5803.

In embodiments where tool 5800 may be used to temporarily expand a nervecuff electrode for implantation purposes, the nerve cuff electrode,e.g., nerve cuff electrode 5810, may be provided with one more geometricconfigurations for facilitation connection with tool 5800. In thedepicted embodiment, nerve cuff electrode 5810 may be provided withextensions 5811, 5812 for facilitating connection with tool 5800. Eachextension 5811, 5812 may be provided with openings 5811 a, 5812 a,respectively, for receiving hook-like projections 5804 a, 5805 a, so asto operably couple nerve cuff electrode 5811 with tool 5800.

Description of Miscellaneous Alternatives

The implanted neurostimulation system may be configured so thatstimulation of the nerve is set at a relatively low level (i.e., lowvoltage amplitude, narrow pulse width, lower frequency) so as tomaximize battery life of the INS and to minimize the chances that theelectrical stimulation will cause arousal from sleep. Ifapneas/hypopneas are detected, then the electrical stimulation can beincreased progressively until the apneas/hypopneas are no longerdetected, up to a maximum pre-set stimulation level. This auto titrationmay automatically be reset to the low level after the patient isawakened and sits up (position detector) or manually reset using thepatient controller. The stimulation level may be automatically reducedafter a period of time has elapsed with no (or few) apneas/hypopneasdetected.

The stimulation level (i.e., voltage amplitude, pulse width, frequency)may be adjusted based on changes in respiration rate. Respiration rateor patterns of rate change may be indicative of sleep state. A differentpower level based on sleep state may be used for minimal powerconsumption, minimal unwanted stimulation (sensory response), etc.,while providing adequate efficacy.

The electrical field shape used to stimulate the target nerve can bechanged while the system is proving therapy based on feedback indicatingthe presence (or lack) of apneas/hypopneas. The electrical field shapefor an implanted system can be changed by adjusting the polarity,amplitude and other stimulation intensity parameters for each of theelectrodes within the nerve stimulating cuff. An algorithm within theINS may change the currently operating electrical field shape if thepresence of apneas/hypopneas is detected, and then wait a set period oftime to determine if the new configuration was successful in mitigatingthe apneas/hypopneas before adjusting the field shape again.Additionally, the system may be designed to keep a log of the mostsuccessful stimulation patterns and when they were most likely to beeffective. This may allow the system to “learn” which settings to beused during what part of the night, for example, or with specificbreathing patterns or cardiac signal patterns or combinations thereof.

The proportion of stimulation intensity of two electrode cuffs used tostimulate a nerve can be modulated while the system is providing therapybased on feedback indicating the presence (or lack) of apneas/hypopneas.For example, one nerve stimulating electrode cuff may be place on themore proximal section of the hypoglossal nerve, while a second is placedmore distally. The proximal cuff will be more likely to stimulatebranches of the hypoglossal nerve going to muscles in the upper airwayinvolved with tongue or hyoid retrusion while the more distal electrodecuff will more likely stimulate only the muscles involved withtongue/hyoid protrusion. Research suggests that to best maintain upperairway patency, stimulating both protrudes and retruders (in the rightproportion) may be more effective that stimulating protruders alone.Software within the INS may change the currently operating proportion ofelectrical stimulation going to the distal electrode cuff in proportionto that going to the proximal cuff based on the presence ofapneas/hypopneas detected. The system may then wait a set period of timeto determine if the new configuration was successful in mitigating theapneas/hypopneas before adjusting the system again. Additionally, thesystem software may be designed to keep a log of the most successfulstimulation proportion and when they were most likely to be effective.This may allow the system to “learn” which settings to be used duringwhat part of the night, for example, or with specific breathing patternsor cardiac signal patterns or combinations thereof.

The system described above may modulate electrical stimulation intensityproportion based on electromyogram (EMG) feedback from the muscles inthe upper airway being stimulated or others in the area. This feedbackmay be used to determine the correct proportion of stimulation betweenprotruders and retruders. The correct ratio of EMG activity betweenretruders and protruders may be determined during a sleep study for anindividual, may be determined to be a constant for a class of patientsor may be “learned” my the implanted system by using the detection ofapneas/hypopneas as feedback.

A library of electrical stimulation parameter settings can be programmedinto the INS. These settings listed in the library may be selected bythe patient manually using the patient programmer based on, for example:(1) direct patient perception of comfort during stimulation; (2) a logof the most successful settings compiled by the software in the INS(assumes apnea/hypopnea detection capability); (3) a sleep physician'sor technician's assessment of the most effective stimulation asdetermined during a sleep study; and/or (4) a list of the most effectiveparameters produced for a particular class of patient or other.

The electrical stimulation parameters described above may be adjustedbased on patient position as detected by a position sensor within theINS. The best setting for a given position may be determined by, forexample: (1) a log of the most successful settings compiled or learnedby the software in the INS (assumes apnea/hypopnea detectioncapability); (2) a sleep physician's or technician's assessment of themost effective stimulation as determined during a sleep study; and/or(3) a list of the most effective parameters produced for a particularclass of patient or other.

To avoid fatigue using a normal duty cycle or to extend the time thatthe upper airway is opened through neurostimulation, different parts ofthe genioglossus muscle and/or different muscles involved withestablishing patency of the upper airway can be alternately stimulated.For example, using two or more nerve or muscle electrode cuffs, the leftand right side genioglossus muscles can be alternately stimulated,cutting the effective duty cycle on each muscle in half. In addition,different protruder muscles on the ipsilateral side such as thegeniohyoid and the genioglossus muscle can be alternately stimulated tothe same effect. This may also be accomplished through one electrodecuff using field steering methods that selectively stimulated thefascicles of the hypoglossal nerve going to one group of protrudersalternating with stimulating the fascicles leading to a differentprotruder muscle group. This method may also be used to alternatelystimulate one group of muscle fibers within the genioglossus muscle withthe compliment of muscle fibers in the same muscle group.

To increase the ability of the upper airway to open during a (sensed)apnea/hypopnea through neurostimulation, different parts of thegenioglossus muscle and/or different muscles involved with establishingpatency of the upper airway can be simultaneously stimulated. Forexample, using two or more nerve or muscle electrode cuffs, the left andright side genioglossus muscles can be simultaneously stimulated,greatly increasing the protrusion forces. In addition, differentprotruder muscles on the ipsilateral side such as the geneohyoid and thegenioglossus muscle can be simultaneously stimulated to the same effect.This may also be accomplished through one electrode cuff using fieldsteering methods that selectively stimulated the fascicles of thehypoglossal nerve going to one group of protruders simultaneously withstimulating the fascicles leading to a different protruder muscle group.This may be achieved with one electrode cuff using field steering on amore proximal location on the hypoglossal nerve or two or more electrodecuffs, one on each branch going to a muscle involved with maintainingmuscle patency.

A sensor inside the INS (or elsewhere in system implanted) may detectbody position and automatically shut off stimulation when patient sitsup or stands up. This will prevent unwanted stimulation when patient isno longer sleeping. The device may automatically restart the stimulationafter the sensor indicates the patient is again horizontal, with orwithout a delay. The system may also be configured so that thestimulation can only be restarted using the patient controller, with, orwithout a delay.

The respiration signal using impedance and/or EMG/ENG are easily capableof determining heart rate. The stimulation may be interrupted or turnedoff when the heart rate falls outside out a pre-determined acceptablerange. This may be an effective safety measure that will decrease thechance that hypoglossal nerve stimulation will interfere with mitigatingphysiological processes or interventional emergent medical procedures.

Respiration waveforms indicating apneas/hypopneas or of other clinicalinterest may be recorded and automatically telemetered to a bed-sidereceiver unit or patient programmer. Respiration waveforms indicatingfrequent apneas/hypopneas, abnormal breathing patterns, irregular heartrate/rhythm may be recorded and automatically telemetered to a bed-sidedeceiver unit or patient programmer causing an alarm to be issued(audible/visible). The INS status such as low battery or systemmalfunction may also trigger an alarm.

Electrical stimulation intensity could be ramped up for each respirationcycle by increasing amplitude or pulse width from 0 to a set point toprevent sudden tongue protrusion or sudden airway opening causing thepatient to wake up. During inspiration, the system may deliverapproximately 30 pulses per second for a length of time of one to oneand one half seconds, totaling between about 30 and 45 pulses perrespiration cycle. Prior to delivery of these 30 to 45 pulses, amplitudeof each individual therapy pulse (in an added group of pulses) could beramped up from 0 to a set point at a rate of <10% of the amplitudeintended for the active duty cycle or 200 mS, whichever is less. Thepulse width of each individual therapy pulse could be ramped up from 0to a set point at a rate of <10% of the active duty cycle or 200 mS,whichever is less. Each of these ramp methods would require a predictivealgorithm that would stimulate based on the previous inspiration cycle.

Nerves innervating muscles that are involved with inspiration, such asthe hypoglossal nerve, have been shown to have greater electricalactivity during apnea or hypopnea. This signal cannot be easily measuredwhile simultaneously stimulating the same nerve. One method ofstimulating and sensing using the same lead is to interleave a sensingperiod within the stimulation pulse bursts during the duty cycle. Inother words, the sensing period may occur between pulses within thestimulation pulse train. This approach may be used with electrodes/leadsthat directly stimulate and alternately sense on a nerve involved withinspiration or on a muscle involved with inspiration or a combination ofthe two. The approach may allow sensing of apnea/hypopnea, as well astherapeutic stimulation.

From the foregoing, it will be apparent to those skilled in the art thatthe present invention provides, in exemplary non-limiting embodiments,devices and methods for nerve stimulation for OSA therapy. Further,those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

Overall Hypoglossal Nerve Stimulation System

FIGS. 59 and 77 schematically illustrate a hypoglossal nerve stimulation(HGNS) system 100 comprising internal components 1000 and externalcomponents 20000. The HGNS system 100 treats obstructive sleep apnea(OSA) by restoring and/or increasing neuromuscular activity to thegenioglossus muscle via stimulation of the hypoglossal nerve (HGN)synchronous with inspiration to mitigate upper airway collapse duringsleep. Stimulation is generated by an implantable neurostimulator (INS)1100, synchronized with inspiration as measured by the respirationsensing lead (RSL) 1200 using bio-impedance, and delivered to thehypoglossal nerve by a stimulation lead (STL) 1300. A programmer system2100 and a therapy controller 2500 are wirelessly linked to the INS1100. The programmer system 2100 includes a computer 2300, a programmerinterface 2400, and a programmer head 22000. The programmer system 2100is used by the physician to control and program the INS 1100 duringsurgery and therapy titration, and the therapy controller 2500 is usedby the patient to control limited aspects of therapy delivery.

The implanted components 1000 of the HGNS system 100 include the INS1100, STL 1300, and RSL 1200. The INS is designed to accommodate one ortwo STLs 1300 and one or two RSLs 1200. One STL 1300 may be used forunilateral implantation and unilateral hypoglossal nerve stimulation.Two STLs 1300 may be used for bilateral implantation on both the rightand left hypoglossal nerves to enhance the effects of stimulation.Alternatively, a second STL 1300 may be used as a back-up in the eventof re-operation necessitated by failure or suboptimal placement of thefirst STL 1300. Similarly, one RSL 1200 may be used for respirationdetection, but two RSLs 1200 may be used for enhanced sensing capabilityor redundancy. Alternatively, a second RSL 1200 may be used as a back-upin the event of re-operation necessitated by failure or suboptimalplacement of the first RSL 1200. Port plugs (not shown) may be used toseal the unused ports in the header of the INS 1100. If only one STL1300 and one RSL 1200 are to be used, the INS 1100 may be simplified toaccommodate one of each lead, thus reducing the size and complexity ofthe INS 1100, as well as increasing battery longevity. For purposes ofillustration, not limitation, the INS 1100 is shown with two RSLs 1200and one STL 1300.

The INS may also be designed to accommodate one STL 1300 and one RSL1200. One STL 1300 may be used for unilateral implantation andunilateral hypoglossal nerve stimulation. Similarly, one RSL 1200 may beused for respiration detection. Alternative embodiments of the RSL 1200are described below and may be substituted. Therefore, for purposes ofillustration not limitation, the INS 1100 is shown with STL 1300 and abifurcated RSL 1200.

The implanted components 1000 may be surgically implanted with thepatient under general anesthesia. The INS 1100 may be implanted in asubcutaneous pocket inferior to the clavicle over the pectoralis fascia.The distal end of the STL 1300 (cuff 1350) may be implanted on thehypoglossal nerve or a branch of the hypoglossal nerve in thesubmandibular region, and the proximal end of the STL 1300 may betunneled under the skin to the INS 1100. The RSL 1200 may be tunneledunder the skin from the INS 1100 to the rib cage and placed on thecostal margin. The INS 1100 detects respiration via the RSL 1200 usingbio-impedance.

Stimulation Lead (STL)

FIG. 60 schematically illustrates the STL 1300 in more detail. The STL1300 is designed to deliver the stimulation signal from the INS 1100 tothe hypoglossal nerve and includes a proximal connector assembly 1310, amain tubular body 1330, and a distal cuff 1350. The main tubular body ofthe STL includes a sigmoid shaped section 1370 and a distal flexibletransition section 1380 proximal of the cuff. The STL may have a nominaloutside diameter of 0.062 inches to have minimal cosmetic impact, and anominal overall length of 17.7 inches (45 cm) (including cuff) to extendfrom the infraclavicular region (INS) to the submandibular region(hypoglossal nerve) and to accommodate anatomical variation.

The main tubular body 1330 of the STL 1300 is designed to withstandgross neck movement as well as mandibular movement and hypoglossal nervemovement caused by talking, chewing, swallowing, etc. To survive in thishigh fatigue environment, the main tubular body 1330 incorporates ahighly compliant silicone jacket in the form of a sigmoid, and twoconductors 1390 (one for cathode electrodes, one for anode electrodes)each comprising ETFE insulated MP35N multifilament cable disposed insidethe jacket in the form of a bi-filar coil (not visible). This designprovides high fatigue resistance and three-dimensional flexibility(bending and elongation).

The proximal connector assembly 1310 is designed to provide a reliablemechanical and electrical connection of the STL 1300 to the INS 1100. Ithas a number of strain relief elements that enable it to withstandhandling during insertion and removal from the INS 1100, as well asadverse conditions encountered when implanted. The connector assembly1310 includes two in-line stainless steel ring contacts (one for eachconductor 1390) and two silicone ring seals. STL proximal connectorcontacts 1310 may have a nominal outside diameter of about 0.122 inches.Set screws in the header of the INS 1100 bear down on the contacts, andtogether with the ring seals, provide a sealed mechanical and electricalconnection to the INS 1100. As an alternative, wound coil springcontacts may provide mechanical and electrical connections.

More detailed views of the cuff 1350 are shown in FIGS. 61A and 61B,wherein FIG. 61A schematically illustrates the cuff 1350 in isometricview, and FIG. 61B schematically illustrates the cuff 1350 incross-sectional view. The cuff 1350 has a hinged oval-shaped siliconebody (collectively 1352 and 1354) to define an oval lumen 1355 thatprovides secure and gentle retention around the hypoglossal nerve. Thecuff 1350 may be designed to fit the nerve very closely to minimizetissue growth between the electrode and nerve. The cuff is designed tobe self-sizing such that different nerve diameters may be accommodatedsafely. The self-sizing can safely adjust to larger sizes if swellingoccurs. This reduces the likelihood of nerved damage caused by unsafepressures. Thus, the cuff may be available in two sizes to accommodatenerves of different diameter: a small size to accommodate nerves havinga diameter of up to about 2.5-3.0 mm, and a large size to accommodatenerves having a diameter of up to 3.2-4.0 mm. At 3.0 mm nerve diameter,either size cuff will fit the nerve with minimal open space for tissueingrowth. Using a large cuff on a 2.5 mm nerve allows clearance betweenthe nerve and electrode which promotes capsule formation between thecuff and nerve. This may cause an increase in capture threshold but willnot affect safety. Conversely, a small cuff placed on a large nerveminimizes electrode coverage around the nerve and may fall off withswelling. The short side 1352 (e.g., 4.0 mm long) of the cuff body fitsbetween nerve branches and connective tissue on the deep side of thenerve, thereby minimization nerve dissection. The long side 1354 (e.g.,10.0 mm long) of the cuff body rests on the superficial side of thenerve (where few branches exist) and is connected to the transitionsection 1380 of the main lead body 1330.

A silicone strap 1356 is connected to and extends from the short side1352 of the cuff body. A silicone top plate comprising an integral baseportion 1359 and loop 1358 is attached to and covers the exteriorsurface of the long side 1354 of the cuff body. The strap 1356 freelyslides through the loop 1358, and wraps around the long side 1354 of thecuff body. The strap 1356 is removed from the loop 1358 for placement ofthe cuff 1350 around the nerve and reinserted into the loop 1358 to holdthe cuff 1350 on the nerve. A mark may be disposed on the strap 1356 ofthe small size cuff to indicate that the cuff is too small and that alarger size cuff should be used if the mark does not pass through theloop 1358. The cuff body readily expands along a hinge line 1353(defined at the junction of the short side 1352 to the long side 1354)as well as other portions of the cuff 1350 structure. Expansion of thecuff body accommodates nerves of different diameters and nerve swellingafter implantation, while the strap 1356 remains in the loop 1358 toretain the cuff 1350 on the nerve. In the event of excess nerve swelling(e.g., >50% increase in nerve diameter) or traction from the lead 1300(e.g., as may accidentally occur during implantation), the strap 1356pulls out of the loop 1358 and releases the cuff 1350 from the nerve tominimize the potential for nerve damage.

The cuff body carries four platinum-iridium electrodes 1360 (e.g., 2.0mm² exposed area each for small cuff, 3.0 mm² exposed area each forlarge cuff), with one cathode electrode 1360 on the short side 1352,another cathode electrode 1360 (not visible) diametrically opposed onthe long side 1354, and two anode electrodes 1360 guarding the cathodeelectrode 1360 on the long side 1354. This guarded dual cathodearrangement provides a more uniform electrical field throughout thecross-section of the nerve while minimizing electrical field outside ofthe cuff. One conductor 1390 may be connected to the cathode electrode1360 on the long side, to which the other cathode electrode 1360 on theshort side is connected by a jumper wire. Similarly, the other conductor1390 may be connected to the distal anode electrode 1360, to which theproximal anode electrode 1360 is connected by jumper wire. With thisarrangement, the cathode electrodes are commonly connected to oneconductor 1390 and the anode electrodes are commonly connected to theother conductor 1390.

With the exception of the metal electrode contacts in the cuff, allexternal surfaces of the STL 1300 exposed to the body when implanted maycomprise implantable grade polymers selected from the following:silicone, and fully cured silicone adhesive. The metal electrodecontacts in the cuff may comprise implantable grade platinum-iridium andare secured to the silicone cuff body with silicone adhesive, forexample.

Respiration Sensing Lead (RSL)

FIGS. 62A and 62B schematically illustrate the respiration sensing lead1200 in more detail. The respiration sensing lead 1200 is designed tomeasure bio-impedance and includes a proximal connector assembly 1210, amain tubular body 1220, and two distal ring electrode pairs 1260. Themain tubular body 1220 of the RSL 1200 includes a proximal sigmoidsection 1230 and a distal sigmoid section 1240 between the electrodepairs 1260. The RSL 1200 may have a nominal outside diameter of 0.072inches to have minimal cosmetic impact, and an overall length of 24.3inches (61.6 cm) unstretched, 32.0 inches (81.3 cm) stretched to extendfrom the infraclavicular region (where the INS 1100 is implanted) to theright or left rib cage (where the RSLs 1200 may be implanted) and toaccommodate anatomical variation.

The main tubular lead body 1220 of the RSL 1200 is designed to withstandthoracic movement due to flexion, extension, rotation and breathing. Towithstand this environment, the main tubular body 1220 may include aflexible silicone jacket formed into two sigmoid sections 1230, 1240 andfour conductors comprising small diameter ETFE insulated MP35NLT wires(not visible) disposed inside the jacket in the form of a quad-filarcoil. The proximal sigmoid section 1230 isolates movement of the INS1100 from the electrode pairs 1260 and accommodates anatomic variationsin thoracic length. The distal sigmoid section 1240 allows adjustment inthe distance between electrode pairs 1260 and reduces strain appliedbetween the anchor tabs 1270, which may be secured with sutures to theunderlying fascia when implanted. The proximal sigmoid 1230 section mayhave 31/2 wavelengths with a peak-to-peak dimension of approximately0.94 inches (2.4 cm) and an overall length of 5.5 inches (14.0 cm). Thedistal sigmoid 1240 section may have 21/2 wavelengths with apeak-to-peak dimension of approximately 0.94 inches (2.4 cm) and anoverall length of 5.5 inches (14.0 cm).

The two distal electrode pairs 1260 may comprise four electrodes total,and each may comprise MP35N rings having an exposed surface area of 28.0mm², for example. As shown in FIG. 62B, tubular strain relief segments1262 and 1272 may be disposed on the lead body on either side of eachelectrode 1260. Where the strain relief segments 1262 and 1272 areadjacent each other, a gap may be provided there between as shown inFIG. 62B or the segments may abut each other to avoid a stressconcentration point. The anchor tab 1270 may be disposed over anelectrode as shown in FIG. 62B leaving the proximal and distalextremities of the electrode exposed.

At any given time, the INS 1100 detects impedance along a vector, witheach end of the vector defined by one active pair of electrodes 1260. Ineach active pair of electrodes 1260, one electrode delivers a smallexcitation current, and the other electrode monitors the correspondingchange in voltage. The INS 1100 may also act as a current emittingand/or voltage sensing electrode. Changes in impedance are calculated bydividing the change in voltage by the excitation current, whichcorrespond to movement of the diaphragm and lung to produce a signalindicative of respiratory activity.

The proximal connector assembly 1210 of the RSL 1200 is designed toprovide a reliable mechanical and electrical connection of the RSL 1200to the INS 1100. It has a number of strain relief elements that enableit to withstand handling during insertion and removal from the INS 1100,as well as adverse conditions encountered when implanted. The connectorassembly 1210 may include four in-line stainless steel ring contacts(one for each conductor) and four silicone ring seals. Set screws in theheader of the INS 1100 bear down on the contacts, and together with ringseals, provide a sealed mechanical and electrical connection to the INS1100.

With the exception of the distal electrodes, all external surfaces ofthe RSL 1200 exposed to the body when implanted may comprise implantablegrade polymers selected from the following: silicone, and fully curedsilicone adhesive. The distal electrodes may comprise implantable gradeMP35N and are sealed to the lead body with silicone adhesive, forexample.

FIG. 62C schematically illustrates an alternative embodiment of therespiration sensing lead 1200. In this embodiment, the RSL 1200 may havea nominal outside diameter of 0.072 inches to have minimal cosmeticimpact, and an overall length of 23.5 inches (59.7 cm) unstretched, 26.5inches (67.2 cm) stretched. The proximal sigmoid 1230 section may have31/2 wavelengths with a peak-to-peak dimension of approximately 0.94inches (2.4 cm) and an overall length of 5.5 inches (14.0 cm). Thedistal sigmoid 1240 section may have ½ wavelength with an amplitude ofapproximately 1.7 inches (4.4 cm) and an overall length of about 0.5inches (1.3 cm).

FIGS. 78A-78G schematically illustrate the respiration sensing lead(RSL) 1200 in more detail. The respiration sensing lead 1200 is designedto measure bio-impedance and includes a proximal portion with a proximalconnector assembly 1210, a proximal tubular body 1220 ending in abifurcation section 1280, and ipsi-lateral and contra-lateral distalportions extending from the bifurcation section. Each distal portion mayinclude a tubular body 1220, a proximal sigmoid section 1230, a distalsigmoid section 1240, one or more current injection ring electrodes1250, one or more voltage sensing ring electrodes 1260, anchor tabs1270, and a suture hole 1290 in the most distal ring electrodes.Alternatively, the ring electrodes 1250 and 1260 may be dual-function,such that each electrode may function as either a current emittingelectrode or voltage sensing electrode. The ipsi-lateral distal portionmay contain three ring electrodes, the most distal being a currentemitting electrode 1250 and containing a suture hole 1290, and the othertwo electrodes being voltage sensing electrodes 1260. The contra-lateraldistal portion may contain two ring electrodes, the distal being acurrent emitting electrode 1250 and containing a suture hole 1290, andthe proximal a voltage sensing electrodes. It may be advantageous tohave the suture holes in the most distal ring electrodes since no wirespass through this point and because this provides a robust anchor pointfor the electrode to be sutured on the costal margin muscle fascia. TheRSL 1200 may have a nominal outside diameter of about 0.072 inches tohave minimal cosmetic impact. The RSL proximal connector contacts 1210may have a nominal outside diameter of about 0.122 inches (same as theSTL proximal connector contacts 1310). The distal ring electrodes (here,current emitting electrodes 1250), may also have a nominal outsidediameter of 0.122 inches. This uniformity in diameters may beadvantageous, allowing the same lead carrier 3100 to place both STL 1300and RSL 1200 leads for tunneling.

The distance from the tip of the proximal connector 1210 to thebifurcation section 1280 may have an overall length of 8.9 inches (22.5cm). The distance from the bifurcation section 1280 to the ipsi-lateralproximal anchor tab 1270 may be 9.6 inches (24.4 cm) unstretched and12.2 inches (31 cm) stretched. The distance from the bifurcation section1280 to the contra-lateral proximal anchor tab 1270 may be 13.5 inches(34.3 cm) unstretched and 16.1 inches (41 cm) stretched. The distancefrom the proximal anchor tab 1270 to the distal suture hole 1290 may be2.8 inches (7 cm) unstretched and 3.1 inches (8 cm) stretched on boththe contra-lateral and ipsi-lateral distal portions. The RSL 1200 mayextend from the infraclavicular region (where the INS 1100 is implanted)to the ipsi-lateral and contra-lateral thorax where the RSL 1200 may beimplanted to accommodate anatomical variation.

The bifurcated RSL 1200 design enables one RSL 1200 to sensebio-impedance on the contra-lateral and ipsi-lateral sides of thethorax. Two RSLs 1200, one on each side of the patient's chest, may alsoachieve this. The bifurcated design achieves this result while reducingthe number of implanted components and reducing volume of the INS header1110 since only one RSL port 1112 is required.

The main tubular lead body 1220 of the RSL 1200 is designed to withstandthoracic movement due to flexion, extension, rotation and breathing. Towithstand this environment, the main tubular body 1220 may include aflexible silicone jacket formed such that each distal end has twosigmoid sections, 1230 and 1240, and conductors comprising smalldiameter ETFE insulated MP35NLT cables (not visible) disposed inside thejacket. An injection molded Y-fitting (yoke) connects the proximalportion of the RSL 1200 to the distal portions, creating the bifurcationsection 1280. Conductors, here five, are continuously fed from theconnector assembly through the proximal tubing body 1220 and proximalportion of the Y-fitting. Three of these conductors continue through theipsi-lateral distal portion of the Y-fitting to the ipsi-lateral distaltubing body of the RSL. The other two conductors continue through thecontra-lateral distal portion of the Y-fitting and to the contra-lateraldistal tubing body of the RSL. The tubing bodies may be adhesivelybonded or molded to the Y-fitting. The number of conductors may equalthe number of contacts in the INS header 1112, here five. Two of theconductors, one on each side, may connect proximally to current emittingheader contacts, (e.g., R1 and L1), and terminate distally in currentemitting electrodes 1250. Three of the conductors may connect proximallyto voltage sensing header contacts (e.g., R2, R3, and L3) and terminatedistally in voltage sensing electrodes. As mentioned previously,dual-function electrodes may enable any electrode (ring electrode 1250or 1260) to emit current or sense voltage. This switching may occur viacomponents on the INS circuit board 1130. Alternatively, a bridge may beformed joining two contacts in the proximal connector assembly such thatthe corresponding electrode may function as either a current emittingelectrode 1250 or voltage sensing electrode 1260. Dual-functionelectrodes enable more vectors in an implanted region without additionalelectrodes.

The proximal sigmoid section 1230 isolates movement of the INS 1100 fromthe electrodes 1250 and 1260, and accommodates anatomic variations inthoracic length. The distal sigmoid section 1240 allows adjustment inthe distance between electrodes 1250 and 1260, and reduces strainapplied between the anchor tabs 1270, which may be secured with suturesto the underlying fascia when implanted. The proximal sigmoid 1230section may have 5 wavelengths with an outside peak-to-peak dimension ofapproximately 0.84 inches (2.1 cm) and an overall length of 7.0 inches(17.8 cm). The distal sigmoid 1240 section may have half a wavelengthwith a center-to-center peak-to-peak dimension of approximately 0.43inches (2.1 cm) and an overall length of 0.869 inches (2.2 cm).

The two distal portions' electrodes 1250 and 1260 may comprise fiveelectrodes total, and each may comprise MP35N rings having an exposedsurface area. The distal electrode containing a suture hole 1290 mayhave an exposed surface area of 73.8 mm² including the suture hole 1290,and 66.4 mm² not including the suture hole 1290. The proximal electrodecontaining an anchor tab 1270 may have an exposed surface area of 30.5mm² and the electrode without an anchor tab may have an exposed surfacearea of 32.0 mm². Tubular strain relief segments may be disposed on thelead body on either side of electrode 1250 or 1260. Where the strainrelief segments are adjacent to each other, a gap may be provided therebetween the strain relief segments or the segments may abut one anotherto avoid a stress concentration point. Strain reliefs may also bedisposed on each end of the electrodes 1250 or 1260 to avoid stressconcentration points. The anchor tab 1270 may be disposed over anelectrode leaving the proximal and distal extremities of the electrodeexposed.

At any given time, the INS 1100 detects impedance along a vector, witheach end of the vector defined by a current delivery electrode 1250 anda voltage sensing electrode 1260. In each vector, a small excitationcurrent is delivered between the two current emitting electrodes 1250,and the corresponding change in voltage is measured by the two voltagesensing electrodes 1260. The INS housing 1120 may also act as a currentemitting and/or voltage sensing electrode, or contain smaller currentemitting and/or voltage sensing electrodes on its surface. Changes inimpedance are calculated by dividing the change in voltage by theexcitation current, which correspond to movement of the diaphragm, lung,and other tissues to produce a signal indicative of respiratoryactivity.

The proximal connector assembly 1210 of the RSL 1200 is designed toprovide a reliable mechanical and electrical connection of the RSL 1200to the INS 1100. It has a number of strain relief elements that enableit to withstand handling during insertion and removal from the INS 1100,as well as adverse conditions encountered when implanted. The connectorassembly 1210 may include five in-line stainless steel ring contacts(one for each conductor) and five silicone ring seals. Set screws in theheader of the INS 1100 bear down on the contacts, and together with ringseals, provide a sealed mechanical and electrical connection to the INS1100. Ring seals may be part of the RSL 1200 or the INS header 1110.With the exception of the distal electrodes, all external surfaces ofthe RSL 1200 exposed to the body when implanted may comprise implantablegrade polymers selected from the following: silicone, and fully curedsilicone adhesive. The distal electrodes may comprise implantable gradeMP35N and are sealed to the lead body with silicone adhesive, forexample.

A wide variety of respiration sensing lead designs may be employed toprovide at least one bio-impedance vector (current injection electrodepair and voltage sensing electrode pair) from a point along the costalmargin to a point along the opposite (trans-lateral) costal margin, to apoint along the same side (ipsi-lateral) costal margin, or to a point inthe infraclavicular region, as seen in FIG. 78C. For example, analternative embodiment of the RSL 1200 is shown in FIG. 78B, wherein thebifurcation section 1280 and contra-lateral distal portion areeliminated. In this three electrode straight RSL 1200 embodiment, thereis one current emitting ring electrode 1250 and two voltage sensing ringelectrodes 1260. The lead body may contain three conductors. Theconnector assembly 1210 may include three in-line stainless steel ringcontacts (one for each conductor) and three silicone ring seals. The RSLmay have an overall length of 21.2 inches (53.9 cm). The distance fromthe proximal tip of the proximal connector assembly 1210 to the firstsigmoid may be 9.5 inches (24.1 cm). The proximal sigmoid 1230 sectionmay have 5 wavelengths with an outside peak-to-peak dimension ofapproximately 0.84 inches (2.1 cm) and an overall length of 7.0 inches(17.8 cm). The distal sigmoid 1240 section may have a ½ wavelength witha center-to-center peak-to-peak dimension of approximately 0.43 inches(2.1 cm) and a length of 0.869 inches (2.2 cm). The RSL 1200 may beimplanted ipsi-laterally on the ipsi-lateral costal margin, a lessinvasive surgery, while maintaining vectors from the ipsi-lateral costalmargin to the infraclavicular region, see FIG. 78D.

Further alternative embodiments are illustrated in FIGS. 78E, 78F, 78G,and 78H, wherein the RSL 1200 may contain four electrodes, one or moreof which can function as either a current emitting electrode 1250 orvoltage sensing electrode 1260, as described previously. Here, this isachieved by exposing the conductor of the bi-functional electrode to twocontacts (one voltage sensing, one current emitting) in the INS header1110, and selecting only one contact for sensing. Alternatively, thisfunctionality may be built into the INS circuit board 1130. Theseembodiments of the RSL 1200 may be implanted ipsi-laterally (e.g. on theright costal margin), which is a less invasive surgery, whilemaintaining vectors from the ipsi-lateral costal margin to theinfraclavicular region.

FIG. 78E illustrates a straight four electrode RSL 1200. This is similarin design to the RSL 1200 of FIG. 78B, wherein there are a first,second, third, and fourth electrodes, from proximal to distal.

FIG. 78F illustrates a four electrode RSL 1200 with a loop back region1255. This differs from the above embodiments in that there is an extrahalf sigmoid in the proximal sigmoid section 1230 after which the leadbody enters the loop back region 1255. Here, the lead body runs in themedial direction, then loops back in the lateral direction. The loopback region 1255 may act as a strain relief and allow the medial anchortab 1270 to be sutured at the intersection of the two tunneling paths(from INS incision to medial incision, and between two RSL incisions).This may allow the RSL 1200 to lie in an unbiased preferredconfiguration along the costal margin. Here again, the first and thirdmost distal electrodes are current emitting, and the second, third, andfourth most distal electrodes are voltage sensing.

FIG. 78G illustrates a four electrode RSL 1200 with a bifurcationsection 1280 created by a T-fitting. An injection molded T-fittingconnects the proximal portion of the RSL 1200 to the distal portions,creating the bifurcation section 1280. Conductors, here four, arecontinuously fed from the connector assembly through the proximal tubingbody 1220 and proximal portion of T-fitting. Two of these conductorscontinue through the proximal distal portion of the T-fitting to theproximal distal tubing body of the RSL. The other two conductorscontinue through the medial distal portion of the T-fitting and to themedial distal tubing body of the RSL. The tubing bodies may beadhesively bonded or molded to the T-fitting. The anchor tab 1270 may beadhesively bonded to the bifurcation section 1280. Again, this may allowthe RSL 1200 to lie in an unbiased preferred configuration along thecostal margin. In addition, the T-fitting may act as a strain relief.Both medial and lateral distal electrodes may contain suture holes 1290.

FIG. 78H illustrates an alternative embodiment of the RSL 1200, whereinthe RSL 1200 has an overall L-shape. In this embodiment, there may befour ring electrodes, numbered one through four from most proximal tofurthest distal. The first and fourth electrodes may be current emittingelectrodes 1250. The second and third electrodes may be voltage sensingelectrodes 1260. The lead body may contain four conductors. Theconnector assembly 1210 may include four in-line stainless steel ringcontacts (one for each conductor) and four silicone ring seals. Theproximal portion of the RSL 1200 (including the proximal connector andproximal sigmoid) may have an overall length of 17.0 inches (43.2 cm).The distance from the proximal tip of the proximal connector assembly1210 to the first sigmoid may be 11.1 inches (28.1 cm). The proximalsigmoid 1230 section may have 4.5 wavelengths, each wavelength 1.25inches (3.2 cm), and with an outside peak-to-peak dimension ofapproximately 0.84 inches (2.1 cm). The distal portion of the RSL 1200(from the distal end of the proximal sigmoid 1230 to the distal suturehole 1290) may have an overall length of 4.9 inches (12.5 cm). Thelength from the distal end of the proximal sigmoid 1230 to the proximalend of the distal sigmoid 1240 may be 2.2 inches (5.7 cm). The lengthfrom the distal end of the distal sigmoid 1240 to the distal suture hole1290 may be 1.8 inches (4.6 cm). The distal sigmoid 1240 section mayhave a center-to-center peak-to-peak dimension of approximately 0.92inches (2.3 cm). The RSL 1200 may be implanted ipsi-laterally on theipsi-lateral costal margin, a less invasive surgery, while maintainingvectors from the ipsi-lateral costal margin to the infraclavicularregion.

Implantable Neurostimulator (INS)

FIG. 63A schematically illustrates the INS 1100 in more detail,including a front view, a top view and a side view. The INS 1100 issimilar in certain aspects to commercially available implantable pulsegenerators and implantable neurostimulators, which may be obtained fromsuitable manufacturers such as CCC Medical Devices (Montevideo,Uruguay). The INS 1100 generally includes a header 1110 for connectionof the STL 1300 and RSLs 1200, and a hermetically sealed housing 1120for containing the associated electronics 1130 and battery 1140 (e.g.,WGL 9086).

The electronic circuitry 1130 contained in the INS 1100 enablestelemetry communication with the programmer system 2100 and therapycontroller 2500, detection of respiration via the RSLs 1200,determination of the trigger point for stimulation, and delivery of acontrolled electrical stimulation signal (pulse train) via the STL 1300.The INS 1100 also records therapy data (device settings, respirationdata, stimulation delivery data, etc.).

The header 1110 may comprise epoxy that is hermetically sealed to thehousing 1120. The housing 1120 may comprise titanium. As mentioned inthe context of respiration sensing, the housing 1120 may be used as anelectrode for bio-impedance respiration measurement. For example, thehousing 1120 may comprise a combination current emitting and voltagesensing electrode for respiration detection.

The header 1110 includes four ports: two RSL ports 1112 (labeled “sense”A and B) for receiving the proximal connectors of up to two RSLs 1200and two STL ports 1114 (labeled “stim” 1 and 2) for receiving theproximal connectors of up to two STLs 1300. Each port that is configuredto receive a STL 1300 includes two set screws (labeled “−” for cathodeand “+” for anode) with associated set screw blocks and seals formechanical and electrical connection to corresponding contacts on theproximal connector 1310 of the STL 1300. Similarly, each port that isconfigured to receive a RSL 1200 includes four set screws (two labeled“I” for current emitting electrodes and two labeled “V” for voltagesensing electrodes) with associated set screw blocks and seals formechanical and electrical connection to corresponding contacts on theproximal connector 1210 of the RSL 1200. The header 1110 furtherincludes two suture holes 1116 (only one is visible) for securing theINS 1100 to subcutaneous tissue such as muscle fascia using sutures whenimplanted in a subcutaneous pocket. As shown, approximate dimensions,component values and component configurations are given by way ofexample, not limitation.

The INS 1100 generates the stimulation output for delivery to thehypoglossal nerve by way of the STL 1300. For this purpose, the INS 1100has two bipolar stimulation output channels, one channel correspondingto each STL port 1114, with each channel providing a pulse train ofconstant current with a frequency range of 20 to 50 Hz, a pulse widthrange of 30 to 215.mu.s, an amplitude range of 0.4 to 5.0 mA, and astimulation duty cycle range of 41%-69%, by way of example, notlimitation.

The INS 110 also generates the excitation signal and measures voltage byway of the RSLs 1200 for bio-impedance respiration detection. For thispurpose, the INS 1100 also has two respiration sensing channels, onechannel corresponding to each RSL port 1112, with each channel providinga small excitation current (“I”) and measuring voltage (“V”). Theexcitation signal may comprise a 10 Hz biphasic constant current pulse,with the positive and negative phases of each biphasic pulse having anamplitude of 300.mu.A, a duration of 50.mu.s, and a charge of 15 nC.Changes in impedance (“Z”) are calculated by dividing the change inmeasured voltage (“V”) by the excitation current (“I”), whichcorresponds to movement of the diaphragm, lung, and other structures toproduce a signal indicative of respiratory activity.

With reference to FIG. 63B, a block diagram of an example of the INScircuit 1130 is shown schematically. The INS circuit 1130 utilizes amicroprocessor to control telemetry communications with the programmersystem 2100, operating the sensing circuits to monitor respiration viathe RSLs 1200, controlling the delivery of output stimuli via the STLs1300, monitoring the magnetically sensitive reed switch and thereal-time clock. The microprocessor contains built-in support circuits(RAM, Flash Memory, Analog to Digital (A/D) Converter, Timers, SerialPorts and Digital IO) used to interface with the rest of the INS circuit1130. The microprocessors. Two microprocessors communicating via aserial link may be used instead of one microprocessor, with the firstmicroprocessor for telemetry communications, monitoring the magneticallysensitive reed switch and the real-time clock; and the secondmicroprocessor for operating the sensing circuits and controlling thedelivery of output stimuli.

The telemetry interface circuits consist of a tuned telemetry coilcircuit and a telemetry driver/receiver circuit to allow pulse encodedcommunication between the external programmer system 2100 and themicroprocessor. As an alternative to telemetry coils and an inductivelink, RF antennae with associated circuitry may be used to establish aRF link to provide for arms-length telemetry. The reed switch provides ameans for the INS 1100 to be controlled by using a magnet placed inclose proximity thereto. The real-time clock provides the basic timebase (32 KHz) for the INS circuit 1130 as well as a clock (year, day,hour, minute, second) which can be used to control the scheduleddelivery of therapy. The clock is also used to time-stamp informationabout the operation of the system that is recorded on a nightly basis.

The respiratory sensing circuits comprise two main parts: the excitationcurrent source (output) and the voltage sensing circuit (input). As willbe described in more detail hereinafter, respiration is detected via theRSLs 1200 using a 4-wire impedance measurement circuit, where anexcitation current is driven through a pair of electrodes, and theresulting voltage is measured on a separate pair of electrodes.Electrode switching circuits (one for each RSL 1200) allows the INS 1100to monitor one of several different vectors from the two separate 4electrode RSLs 1200. The INS housing 1120 may also be used as both anexcitation and sensing electrode. The excitation current circuitdelivers biphasic pulses of low level (300 uA) current to the selectedelectrode pair every 100 ms during sensing. The voltage sensingamplifier circuit synchronously monitors the voltage produced by theexcitation current on the selected electrode pair. The resulting outputsignal is proportional to the respiratory impedance (0.20 to 10.OMEGA.)and is applied to the A/D circuit in the microprocessor for digitizationand analysis.

The stimulation output circuits deliver bursts of biphasic stimulationpulses to either STL 1300. These bursts may be synchronized to thesensed respiratory waveform. The stimulation output circuits include anelectrode switching network, a current source circuit, and an outputpower supply. The electrode switching network allows selection of thestimulation output channel (pair A or B), each corresponding to a STL1300. The electrode switching network also allows for a charge balancingcycle following each stimulation pulse during which the outputs areconnected together with no applied output pulse. The timing and polarityof the pulse delivery is provided by control outputs of themicroprocessor. The microprocessor selects the amplitude (e.g., 0.5 mAto 5 mA) of the output current from the current source circuit which isapplied through the switching network. The output power supply convertsbattery voltage to a higher voltage (e.g., 5V to 13V) which issufficient to provide the selected current into the load impedance ofthe STL 1300. The microprocessor measures the voltage output from theelectrode switching network resulting from the delivered current and theload impedance. The microprocessor divides the output voltage by theoutput current resulting in a measure of the load impedance (600.OMEGA.to 2500.OMEGA.) which can be an indicator of integrity of the STL 1300.

With reference to FIG. 64A, the bio-impedance respiration signal (“Z”),which is generated by dividing the change in measured voltage (“V”) bythe excitation current (“I”), tracks with diaphragm movement (DM) overtime and therefore is a good measure of respiratory activity, and may beused to measure respiratory effort, respiratory rate, respiratory(tidal) volume, minute volume, etc. If the excitation current (I) isconstant or assumed constant, then the bio-impedance (Z) is proportionalto the measured voltage (V), and thus the voltage (V) may be used as asurrogate for bio-impedance (Z), thereby eliminating the division step.As used in this context, diaphragm movement includes movements and shapechanges of the diaphragm and adjacent tissue that occur during normalbreathing and during obstructed breathing. The (positive or negative)peak (P) of the impedance signal (Z) corresponds to the end of theinspiratory phase and the beginning of the expiratory phase. If thesignal is normal (as shown), the positive peak is used; and if thesignal is inverted, the negative peak is used. The beginning of theinspiratory phase occurs somewhere between the peaks and may not bereadily discernable. Thus, the impedance signal provides a reliablefiducial (P) for end-inspiration and begin-expiration (also calledexpiratory onset), but may not provide a readily discernable fiducialfor begin-inspiration (also called inspiratory onset). Therefore,algorithms described herein do not rely on begin-inspiration (orinspiratory onset) for triggering stimulation as proposed in the priorart, but rather use a more readily discernable fiducial (P)corresponding to begin-expiration (or expiratory onset) in a predictivealgorithm as described below. Other non-predictive (e.g., triggered)algorithms are described elsewhere herein.

In people without OSA, the hypoglossal nerve usually activatesapproximately 300 ms before inspiration and remains active for theentire inspiratory phase. To mimic this natural physiology, it isdesirable to deliver stimulation to the hypoglossal nerve during theinspiratory phase plus a brief pre-inspiratory period of about 300 ms.As mentioned previously, a reliable fiducial for the beginning of theinspiratory phase may not be available from the impedance signal, and areliable fiducial for the pre-inspiratory period may not be availableeither. However, there are reliable fiducials for the beginning of theexpiratory phase (peak P) which may be used to trigger stimulation tocover the inspiratory phase plus a brief pre-inspiratory period.

Accordingly, an algorithm is used to predict respiratory period anddetermine stimulation trigger time. The predictive algorithm iscontained in software and executed by a microprocessor resident in theINS circuitry 1130, thus enabling the INS 1100 to generate stimulationsynchronous with inspiration.

One example of a predictive algorithm is illustrated in FIG. 64B. Inthis example, the stimulation period is centered about a percentage(e.g., 75%) of the predictive respiratory period. The predictivealgorithm uses historical peak data (i.e., begin-expiration data) topredict the time to the next peak, which is equivalent to the predictedrespiratory period. The stimulation period is centered at 75%, forexample, of the predicted respiratory time period. Thus, the stimulationtrigger point is calculated by predicting the time to the next peak,adding 75% of that predicted time to the last peak, and subtracting ½ ofthe stimulation period (trigger time=time of last peak+75% of predictedtime to next peak−½ stimulation period). A phase adjustment parameter(range: −1500 ms to +500 ms, for example) permits the stimulation periodto be biased early or late. A default setting (e.g., −500 ms) of thephase adjustment parameter moves the stimulation period early relativeto the anticipated start of inspiration.

Another example of a predictive algorithm is illustrated in FIG. 64C.This example differs for the example illustrated in FIG. 64B in that thestimulation period is initiated (not centered) at a percentage (e.g.,50%) of the predicted respiratory period. However, the two examples haveessentially equivalent results for a duty cycle of 50%. As in the priorexample, the predictive algorithm uses historical peak data (i.e.,begin-expiration data) to predict the time to the next peak, which isequivalent to the predicted respiratory period. The stimulation periodmay start at 50%, for example, of the predicted time period. Thus, thestimulation trigger point is calculated by predicting the time to thenext peak and adding 50% of that predicted time to the last peak(trigger time=time of last peak+50% of predicted time to next peak). Aphase adjustment parameter (range: −1500 ms to +500 ms, for example)permits the stimulation period to be biased early or late. A defaultsetting (e.g., −500 ms) of the phase adjustment parameter moves thestimulation period early relative to the anticipated start ofinspiration.

A feature common to the predictive algorithms is illustrated in FIG.64D. This feature provides a sequence of predicted respiratory periodsin case the respiration impedance signal (“Z”) is temporarily lost(e.g., due to change in respiratory effort). Until a subsequentrespiratory peak is detected, stimulation parameters which are based onthe measured respiratory period (e.g., stimulation period) areunchanged. Thus, stimulation timing remains synchronous to the lastdetected peak.

The stimulation duty cycle may vary to meet efficacy and safetyrequirements. Generally, the stimulation duty cycle is used to determinethe stimulation period as a percentage of the predicted respiratoryperiod (stimulation period=duty cycle.times.predicted respiratoryperiod). After a stimulation period is started, stimulation continuesuntil the end of the stimulation period as set by the stimulation dutycycle, or until the next actual peak is detected, whichever occursfirst. Note that the result of the algorithm illustrated in FIG. 64B isthe same as the result of the algorithm illustrated in FIG. 64C for astimulation duty cycle of 50%.

The stimulation duty cycle may be fixed or adaptive. In the fixed mode,the stimulation duty cycle is set using to programmer system 2100 to afixed value. This fixed value may be increased when the respiratorysignal is lost. In adaptive mode, the duty cycle is allowed to vary as afunction of a characteristic of respiration. For example, the adaptiveduty cycle may increase with an increase in respiratory periodvariability or with the loss of respiratory signal. Thus, in someinstances, the stimulation duty cycle may run above normal (e.g., above50% to 60%) to achieve a better likelihood of covering the inspiratoryphase. Because above normal stimulation duty cycle may result in nerveand/or muscle fatigue if prolonged, it may be desirable to offsetabove-normal stimulation periods with below-normal stimulation periodsto result in a net normal duty cycle. For example, if a X % stimulationduty cycle is defined as normal and the adaptive mode results in aperiod T1 where the stimulation duty cycle runs Y % more than X %, theabove-normal stimulation period may be proportionally offset by abelow-normal stimulation period T2 where the stimulation duty cycle runsZ % less than X % to satisfy the equation Y.times.T1=Z.times.T2. Thisequation is approximate and may vary slightly depending on the averagingtechnique used. Other offset methods may be used as an alternative.

The following stimulation duty cycle parameters are given by way ofexample, not limitation. In fixed mode, the maximum stimulation dutycycle may be set from 41% to 69% in 3% increments, and the defaultsetting may be 50%. In adaptive mode, the stimulation duty cycle for arespiratory period may vary from 31% to 69% in 3% increments, and themaximum running average may be set to 53%. As mentioned above, theadaptive mode allows the duty cycle to increase with respiratory periodvariability, for example, and the stimulation duty cycle may run inexcess of 53% for a limited period of time, but those periods areproportionally offset by periods where the stimulation duty cycle runsless than 53% (e.g., according to an exponentially weighted movingaverage). For example, an adaptive duty cycle set to 69% would run atthat level for no longer than 5 to 7 minutes before being offset by alower stimulation duty cycle at 47% to result in a running average of53%.

FIG. 79A schematically illustrates the INS 1100 in more detail,including a front view, a top view and a side view. The INS 1100 issimilar in certain aspects to commercially available implantable pulsegenerators and implantable neurostimulators, which may be obtained fromsuitable manufacturers such as CCC Medical Devices (Montevideo,Uruguay). The INS 1100 generally includes a header 1110 for connectionof the STL 1300 and RSLs 1200, and a hermetically sealed housing 1120for containing the associated electronics 1130, a battery 1140 (e.g.,Greatbatch 9086), and an accelerometer 1150. The INS 1100 may contain anoxygen sensor (e.g., SaO₂, SpO₂, ion, etc.). Alternatively, the oxygensensor may be incorporated in a lead with connection to the INS 1100.

The electronic circuitry 1130 contained in the INS 1100 enablestelemetry communication with the programmer system 2100 and therapycontroller 2500, detection of respiration via the RSL 1200,determination of the start time and duration of a stimulation signal,and delivery of a controlled electrical stimulation signal (pulse train)via the STL 1300. The INS 1100 also records therapy history data (devicesettings, status, measured data, device use, respiration data,stimulation delivery data, statistics based on measured signals, etc.).

The header 1110 may comprise epoxy that is hermetically sealed to thehousing 1120. The housing 1120 may comprise titanium. As mentioned inthe context of respiration sensing, the housing 1120 may be used as anelectrode for bio-impedance respiration measurement. Similarly,electrodes 1360 may be used as an electrode for bio-impedancerespiration measurement. For example, the housing 1120 may comprise acombination current emitting and voltage sensing electrode forrespiration detection. Alternatively, separate electrodes may beincluded in the header of the device from which to sense or stimulate.

The header 1110 includes two ports: one RSL port 1112 (labeled “sense”)for receiving the proximal connector of the RSL 1200 and one STL port1114 (labeled “stim”) for receiving the proximal connector of the STL1300. The port configured to receive a STL 1300 includes two set screws(labeled “−” for cathode and “+” for anode) with associated set screwblocks and seals for mechanical and electrical connection tocorresponding contacts on the proximal connector 1310 of the STL 1300.Similarly, the port that is configured to receive a RSL 1200 includesfive set screws (two labeled R1 and L1 for current emitting electrodesand three labeled R2, R3, and L3, for voltage sensing electrodes) withassociated set screw blocks and seals for mechanical and electricalconnection to corresponding contacts on the proximal connector 1210 ofthe RSL 1200. Seals are located between electrical contacts as well asbetween the distal-most electrical contact and the remainder of theproximal connector assembly 1210. These seals electrically isolate eachcontact.

Alternatively, wound coil spring contacts may provide electricalconnections between the INS header 1110 and the proximal connectorassemblies 1210 and 1310. Typically, one electrical connection is stillachieved with a set screw which also serves to hold the connectorassembly in place. This embodiment provides a sealed mechanical andelectrical connection of the RSL 1200 and STL 1300 to the INS 1100. Anexample of this technology is Bal Seal's Canted Coil™ Spring Technology.

The header 1110 further includes two suture holes 1116 for securing theINS 1100 to subcutaneous tissue such as muscle fascia using sutures whenimplanted in a subcutaneous pocket. As shown, component values andcomponent configurations are given by way of example, not limitation.

The INS 1100 generates the stimulation output for delivery to thehypoglossal nerve by way of the STL 1300. For this purpose, the INS 1100has a bipolar stimulation output channel corresponding to the STL port1114, with the channel providing a pulse train of bi-phasic constantcurrent pulses with a frequency range of 20 to 50 Hz, a pulse widthrange of 30 to 215.mu.s, an amplitude range of 0.4 to 5.0 mA, and astimulation duty cycle range of 41%-69%, by way of example, notlimitation.

The INS 1100 also generates the excitation signal and measures voltageby way of the RSL 1200 for bio-impedance respiration detection. For thispurpose, the INS 1100 also has two respiration sensing channels forsimultaneous acquisition of bio-impedance sensing on different vectors.This may be achieved by sequential or alternating sampling of differentvectors. The INS 1100 measures bio-impedance via the RSL port 1112, witheach channel providing a small excitation current (“I”) and measuringvoltage (“V”). The excitation signal may comprise a 10 Hz biphasicconstant current pulse, with the positive and negative phases of eachbiphasic pulse having amplitude of 450.mu.A, duration of 80.mu.s, andcharge of 36 nC. Current (“I”) may be fixed, allowing voltage (“V”) tobe a relative measure of impedance (“Z”), which corresponds to movementof the diaphragm, lung, and other structures to produce a signalindicative of respiratory activity.

With reference to FIG. 79B, a block diagram of an example of the INScircuit 1130 is shown schematically. The INS circuit 1130 utilizes amicroprocessor to control telemetry communications with the programmersystem 2100, operating the sensing circuits to monitor respiration viathe RSL 1200, controlling the delivery of output stimuli via the STL1300, monitoring the accelerometer, magnetically sensitive reed switchand the real-time clock. The microprocessor contains built-in supportcircuits (RAM, flash memory, analog to digital (A/D) converter, timers,serial ports and digital IO) used to interface with the rest of the INScircuit 1130, including the accelerometer 1150. Two microprocessorscommunicating via a serial link may be used instead of onemicroprocessor, with the first microprocessor for telemetrycommunications, monitoring the accelerometer, magnetically sensitivereed switch and the real-time clock; and the second microprocessor foroperating the sensing circuits and controlling the delivery of outputstimuli. Alternatively, a single microprocessor could perform thesefunctions.

The telemetry interface circuits consist of a tuned telemetry coilcircuit and a telemetry driver/receiver circuit to allow pulse encodedcommunication between the external programmer system 2100 and themicroprocessor. As an alternative to telemetry coils and an inductivelink, RF antennae with associated circuitry may be used to establish aRF link to provide for arms-length telemetry. The reed switch provides ameans for the INS 1100 to be controlled by using a magnet placed inclose proximity thereto. The real-time clock provides the basic timebase (768 Hz) for the INS circuit 1130 as well as a clock (year, day,hour, minute, second) which can be used to control the scheduleddelivery of therapy. The clock is also used to time-stamp informationabout the operation of the system that is recorded on a nightly basis.

The respiratory sensing circuit is comprised of two main parts: theexcitation current source (output) and the voltage sensing circuit(input). As will be described in more detail hereinafter, respiration isdetected via the RSL 1200 using a 3 or 4-wire impedance measurementcircuit. In a 4-wire measurement, an excitation current is driventhrough a pair of electrodes, and the resulting voltage is measured on aseparate pair of electrodes. The electrode switching circuits allow theINS 1100 to monitor one of several different vectors from the RSLelectrodes 1250 and 1260. As mentioned previously, each physicalelectrode may function as a current emitting electrode 1250 or a voltagesensing electrode 1260, depending on the programmable vectorconfiguration. In one embodiment of a 3-wire measurement, the INShousing 1120 may be used as both an excitation and sensing electrode.The excitation current circuit delivers biphasic pulses of low level(450 uA) current to the selected electrode pair every 100 ms duringsensing. The voltage sensing amplifier circuit synchronously monitorsthe voltage produced by the excitation current on the selected electrodepair. The resulting output signal is proportional to the respiratoryimpedance (0.071 to 10.OMEGA.) and is applied to the A/D circuit in themicroprocessor for digitization and analysis.

The stimulation output circuits deliver bursts of biphasic stimulationpulses to the STL 1300. These bursts may be synchronized to the sensedrespiratory waveform to deliver stimulation and thus airway opening atthe appropriate time. The stimulation output circuits include anelectrode switching network, a current source circuit, and an outputpower supply. The electrode switching network also allows for a chargebalancing cycle following each stimulation pulse during which theoutputs are connected together with no applied output pulse. The timingand polarity of the pulse delivery is provided by control outputs of themicroprocessor. The microprocessor selects the amplitude (e.g., 0.4 mAto 5 mA) of the output current from the current source circuit which isapplied through the switching network. The output power supply convertsbattery voltage to a higher voltage (e.g., 5V to 14V) which issufficient to provide the selected current into the load impedance ofthe STL 1300. The microprocessor measures the voltage output from theelectrode switching network resulting from the delivered current and theload impedance. The microprocessor divides the output voltage by theoutput current resulting in a measure of the load impedance (400.OMEGA.to 2700.OMEGA.) which can be an indicator of integrity of the STL 1300.

The INS 1100 (or lead connected to the INS 1100) may contain an oxygensensor to monitor oxygen levels, for example during a therapy session.This may be used to monitor efficacy as well to set stimulation settingsduring a therapy session. For example, the INS 1100 may be programmed toincrease stimulation when oxygen de-saturations are detected at aprogrammable threshold rate and/or severity. In addition, the INS 1100may turn stimulation on once de-saturations are detected, whereinthresholds of rate and severity are programmable. Desaturations may actto indicate the sleep state or wakefulness. In a similar manner,electroneurogram (ENG) may be used to monitor nerve activity, which mayalso be indicative of sleep state and/or wakefulness. The INS 1100 mayuse the indication of sleep state or wakefulness to change stimulationsettings. For example, stimulation may be increased when the patient isin N3 or REM sleep. In addition, stimulation level may be decreased orturned off during stage N1, N2, or wakefulness.

The INS 1100 circuitry may contain a three-axis accelerometer 1150 thatcan be used to determine the patient's body position (supine, prone,upright, left, or right side) and/or detect motion events (wakefulness).These data may be used to change stimulation settings or inhibit output.The INS 1100 may be programmed to increase stimulation intensity whenthe patient is in specific body positions (e.g., supine, a morechallenging position). The INS 1100 may segregate recorded therapystatistics (e.g., cycling detector events, oxygen desaturations) withrespect to body position. For example, a patient's cycling detector mayrecord very few events in the lateral position and many events in thesupine position, indicative of the patient being treated in the lateralposition.

With reference to FIG. 80A, the bio-impedance respiration signal (“Z”),which is generated by dividing the change in measured voltage (“V”) bythe excitation current (“I”), tracks with diaphragm movement (DM) overtime and therefore is a good measure of respiratory activity, and may beused to measure respiratory effort, respiratory rate, respiratory(tidal) volume, minute volume, etc. If the excitation current (I) isconstant or assumed constant, then the bio-impedance (Z) is proportionalto the measured voltage (V), and thus the voltage (V) may be used as asurrogate for bio-impedance (Z), thereby eliminating the division step.As used in this context, diaphragm movement includes movements and shapechanges of the diaphragm and adjacent tissue that occur during normalbreathing and during obstructed breathing. The bio-impedance waveformmay be filtered to reduce noise and eliminate cardiac artifact,clarifying positive and negative peak occurrence. The signal may befiltered using a first order low pass filter. Alternatively, a higherorder curve fit approach could be utilized to filter the signal. The(positive or negative) peak (P) of the impedance signal (Z) correspondsto the end of the inspiratory phase and the beginning of the expiratoryphase. If the signal is normal (as shown), the positive peak is used;and if the signal is inverted, the negative peak is used. The beginningof the inspiratory phase occurs somewhere between the peaks and may notbe readily discernable. Thus, the impedance signal provides a reliablefiducial (P) for end-inspiration and begin-expiration (also calledexpiratory onset), but may not provide a readily discernable fiducialfor begin-inspiration (also called inspiratory onset). Therefore,algorithms described herein do not rely on begin-inspiration (orinspiratory onset) to determine the start of stimulation bursts asproposed in the prior art, but rather use a more readily discernablefiducial (P) corresponding to begin-expiration (or expiratory onset) ina predictive algorithm as described below. Other non-predictive (e.g.,triggered) algorithms are described elsewhere herein.

Gross body motion is often indicative of patient wakefulness and maychange the bio-impedance signal (Z). A motion event may be detected, forexample, by assessing variability in the bio-impedance peak-to-peaksignal strength (P-P). Different thresholds of sensitivity may beutilized such that minor movements are not grouped with motion events.When a motion event is determined, stimulation may be turned off orturned down until motion stops or for a programmable duration of time.The frequency and duration of these motion events may be recorded indevice history. The accelerometer 1150 could be utilized in a similarfashion to detect and record motion events.

Waxing and waning of the bio-impedance signal (Z) is often indicative ofapneas or hypopneas. Generally referred to as cycling, this pattern maybe detected, for example, by assessing trends of increasing anddecreasing average P-P amplitude values. Different thresholds ofsensitivity may be utilized such that minor changes in P-P values arenot declared cycling events. When cycling is detected, stimulationparameters may be initiated or changed (e.g., increased intensity,increased duty cycle, etc.) to improve therapy. The frequency andduration of these cyclic breathing patterns may be recorded in therapyhistory. These values may be used as an indicator of how well thepatient is being treated, providing an estimate of AHI.

The INS 1100 may be programmed to change stimulation level betweentherapy sessions, days, or other programmable value. The stimulationlevel may be recorded alongside therapy session data, for examplecycling rate (via the cycling detector), oxygen desaturation frequencyand severity, stimulation time, variations in respiratory rate,variations in respiratory prediction, etc.

In people without OSA, inspiration is typically 25-50% of therespiratory cycle, with variations in respiration rate being common.Variations may cause actual inspiration to differ from predictedinspiration. The hypoglossal nerve usually activates approximately 300ms before inspiration and remains active for the entire inspiratoryphase. To mimic this natural physiology, it is desirable to deliverstimulation to the hypoglossal nerve during the inspiratory phase plus abrief pre-inspiratory period of about 300 ms. To maximize stimulationcoverage of actual inspiration, it may be advantageous to account forthis variability by centering stimulation on the predicted inspiration.As mentioned previously, there are reliable fiducials for the beginningof the expiratory phase (peak P) which may be used to deliverstimulation to cover the inspiratory phase plus brief pre and/orpost-inspiratory periods.

Accordingly, an algorithm is used to predict respiratory period anddetermine the start of the stimulation burst. The predictive algorithmis contained in software and executed by a microprocessor resident inthe INS circuitry 1130, thus enabling the INS 1100 to generatestimulation synchronous with inspiration. One example of a predictionalgorithm uses the respiratory period of previous breaths to predict therespiratory period of each subsequent breath. In this algorithm, arespiratory period is determined by calculating the time between peaksin the bio-impedance signal (Z). If the actual respiratory period isdifferent from the predicted respiratory period, then the subsequentpredicted respiratory period is resynchronized and updated to equal theactual period, up to a programmable value (e.g., 300 ms). If thedifference in respiratory period exceeds the programmable value, thenthe predicted respiratory period is incremented or decremented by thisvalue.

One example of a predictive algorithm is illustrated in FIG. 80B. Inthis example, the stimulation period is centered about a percentage(e.g., 75%) of the predictive respiratory period. The predictivealgorithm uses historical peak data (i.e., begin-expiration data) topredict the time to the next peak, which is equivalent to the predictedrespiratory period. The stimulation period is centered at 75%, forexample, of the predicted respiratory time period. Thus, the time tostart a stimulation burst is calculated by predicting the time to thenext peak, adding 75% of that predicted time to the last peak, andsubtracting ½ of the stimulation period (stimulation start time=time oflast peak+75% of predicted time to next peak−½ stimulation period). Aphase adjustment parameter (range: +/−1000 ms, for example) permits thestimulation period to be biased early or late.

A feature common to the predictive algorithms is illustrated in FIG.80C. This feature provides a sequence of predicted respiratory periodsin case the respiration impedance signal (“Z”) is temporarily lost(e.g., due to change in respiratory effort). Until a subsequentrespiratory peak is detected, stimulation parameters which are based onthe measured respiratory period (e.g., stimulation period) areunchanged. Thus, stimulation timing remains synchronous to the lastdetected peak.

The stimulation duty cycle may vary to meet efficacy and safetyrequirements. Generally, the stimulation duty cycle is used to determinethe stimulation period as a percentage of the predicted respiratoryperiod (stimulation period=duty cycle.times.predicted respiratoryperiod). After a stimulation burst (pulse train) is started, stimulationcontinues until the end of the stimulation burst as set by thestimulation duty cycle, or until the next actual peak is detected,whichever occurs first. Alternatively, the feature of terminating astimulation period when an actual peak is detected may be turned off.

The stimulation duty cycle may be fixed or adaptive. In the fixed mode,the stimulation duty cycle is set using to programmer system 2100 to afixed percentage value. This fixed value may be increased when therespiratory signal is lost, increasing the likelihood of aligning withactual inspiration. In adaptive mode, the duty cycle is allowed to varyas a function of a characteristic of respiration. For example, theadaptive duty cycle may increase when prediction is less accurate(higher variability in respiration rate) or when the respiratory signalis lost. Thus, in some instances, the stimulation duty cycle may runabove normal (e.g., above 50% to 60%) to achieve a better likelihood ofcovering the inspiratory phase. Because above normal stimulation dutycycle may result in nerve and/or muscle fatigue if prolonged, it may bedesirable to offset above-normal stimulation periods with below-normalstimulation periods to result in a net normal duty cycle. Thus, when theprediction is highly accurate (stable respiration rate), the stimulationduty cycle may be reduced.

The following stimulation duty cycle parameters are given by way ofexample, not limitation. In fixed mode, the maximum stimulation dutycycle may be set from 41% to 69% in 3% increments, and the defaultsetting may be 50%. In adaptive mode, the stimulation duty cycle for arespiratory period may vary from 31% to 69% in 3% increments, and themaximum running average may be set to 53%. As mentioned above, theadaptive mode allows the duty cycle to decrease when respiratory periodis stable and increase with respiratory period variability, for example,and the stimulation duty cycle may run in excess of 53% for a limitedperiod of time, but those periods are proportionally offset by periodswhere the stimulation duty cycle runs less than 53% (e.g., according toan exponentially weighted moving average). For example, an adaptive dutycycle set to 69% would run at that level for no longer than 5 to 7minutes before being offset by a lower stimulation duty cycle at 47% toresult in a running average of 53%. This equation is approximate and mayvary slightly depending on the averaging technique used. Other offsetmethods may be used as an alternative.

The stimulation duty cycle may be nominally 50%. A duty cycle limitermay be enabled such that it prevents the device from exceeding aprogrammable long term average stimulation duty cycle threshold (e.g.,53%). Long term average duty cycle may be calculated using a first orderfilter of duty cycle measured over a fixed time period (e.g., 6seconds), with a programmable filter time constant (e.g., each iterativecalculation is given a weighting of 1/32). If the long term average dutycycle reaches the programmable threshold, then stimulation duty cycle isdecreased to a programmable value, (e.g., 44%) until the long termaverage drops below the nominal value (here, 50%), at which time thenominal duty cycle is restored. This safety mechanism may prevent nerveand muscle fatigue.

The INS 1100 may deliver stimulation as a train of pulses with constantpulse width and amplitude at a set frequency for a duration limited byduty cycle. This train of pulses may be described as a pulse trainenvelope and is illustrated in FIG. 80D. The envelope describes a seriesof biphasic pulses delivered consecutively during a stimulation burst.When the stimulation level of the positive phase of each biphasic pulseis uniform, this level is the level of the stimulation burst. The INS1100 may also deliver stimulation in pulse train envelopes wherein thepulses are non-uniform (e.g., pulses may have different amplitudes).

The muscle(s) activated by the stimulation may not require the fullstimulation intensity for the duration of the stimulation in order tomaintain muscle contraction. Accordingly, the INS 1100 may be programmedto deliver a basic retention intensity pulse configuration, defined as apulse train envelope wherein each pulse's intensity (e.g., amplitude) isless than or equal to the previous pulse's intensity, (e.g., a twosecond pulse wherein the first 1000 ms is at 2 mA and the subsequent1000 ms is at 1.7 mA). This pulse configuration is illustrated in FIG.80E. This allows the muscle to activate to a level and then remain inthat position with a less intense stimulation. This may be morecomfortable and allow the patient to fall asleep more easily with thestimulation on, be less likely to cause arousal from sleep, and/orreduce the possibility of muscle/nerve fatigue. Alternatively, the pulselevel (amplitude) could be decreased gradually during each burst (ratherthan abruptly) to reach the same final stimulation level.

A more gradual transition at the start of each burst may be morecomfortable and be less likely to cause arousal from sleep, and/orreduce the possibility of muscle/nerve fatigue. Accordingly, the INS1100 may be programmed to deliver a soft start pulse configuration,defined as a pulse train envelope wherein at the start of each burst,each pulse's intensity (e.g., amplitude) is greater than or equal to theprevious pulse's intensity, (e.g., a two second pulse wherein the first100 ms is at 1.85 mA, the second 100 ms is at 1.95 mA, the third 100 msis at 2.05 mA and the remaining 1700 ms is at 2.1 mA). This pulseconfiguration is illustrated in FIG. 80G. The pulse train envelope wouldthus have a stair-like appearance as stimulation increases to the fullstimulation plateau.

In another embodiment, a pulse train envelope may employ a soft start toreach full stimulation and subsequently decrease intensity (amplitude)to a retention intensity for the remainder of the stimulation, (e.g., atwo second pulse wherein the first 100 ms is at 1.85 mA, the second 100ms is at 1.95 mA, the third 100 ms is at 2.05 mA, and the next 700 ms isat 2.1 mA, and the remaining 1000 ms is at 1.8 mA). This pulseconfiguration is illustrated in FIG. 80F. This configuration may providethe benefits of both soft start and retention intensity, wherein thestimulation starts gradually to fully activate the muscle(s), thendecreases to a level of less intense stimulation, with the muscleremaining in a contracted position. FIG. 80H shows nested mode, asimplified version of the previously mentioned retention intensity,wherein there is one step up to the full amplitude, and then an equalstep down to the retention intensity.

The INS provides two separate stimulation strengths (A & B) withindependent parameters (amplitude, pulse width, frequency, duty cycleand phase adjust). Stimulation may be delivered in different therapymodes, examples of which are shown in FIG. 80I. FIG. 80I (traces 1-8)illustrates some commonly used modes, all of which are inspiratorysynchronous, meaning stimulation is automatically delivered according toan algorithm that predicts the inspiratory phase and initiatesstimulation delivery at a desired time relative to inspiration, such ascentered on the predicted inspiration. These modes may be used asstandard therapy as well as to determine device settings during a PSG(e.g. sleep titration PSG). Additionally, these modes may be used todiagnose phenotypes of OSA or other diseases.

FIG. 80I (trace 1) illustrates synchronous mode in which everystimulation has the same pulse configuration and amplitude, known asAAAA mode, the default therapy mode. The term AAAA mode means that fourconsecutive inspirations are covered by stimulation of level A, where Ais 2.0 mA, for example. Inspiration is shown in FIG. 80I (trace 9) inthe upward direction.

The inspiratory-synchronous ABAB mode, FIG. 80I (trace 2), also deliversstimulation bursts synchronous with inspiration as determined by thedevice, therapy delivery algorithm settings, and sensed respiratorysignal. This mode is similar to AAAA mode, except that the stimulationis delivered on four consecutive inspirations alternating betweenstimulation levels A and B on each burst where, for example, A is 2.0 mAand B is 1.8 mA.

FIG. 80I (trace 3) illustrates a subset of ABAB mode known as A0A0 mode,wherein the B breath is not stimulated. A may be 2.0 mA and B may be 0mA, for example.

FIG. 80I (trace 4) illustrates A0B0 mode, wherein a first breath isstimulated at level “A,” followed by an second breath that isunstimulated, followed by a third breath that is stimulated at level“B,” followed by a fourth breath that is unstimulated, (e.g., A is 2.0mA and B is 1.8 mA). This allows for simultaneous assessment of twodifferent levels (A and B) when compared to adjacent non-stimulatedbreaths.

FIG. 80I (trace 5) illustrates AABB mode wherein two breaths arestimulated at level “A” followed by two breaths stimulated level “B,”(e.g. A is 2.0 mA and B is 1.8 mA). In this mode, every stimulatedbreath is adjacent to a stimulated breath at level “A” and a stimulatedbreath at level “B.” The AABB mode may be used to test if there is ashort-term residual cross-over effect when changing from one stimulationlevel to another stimulation level or from a stimulation level to nostimulation. For example, the airflow measured during the first “A” canbe compared to the airflow measured during the second “A” in eachsequence over many periods to determine if there is a measurableresidual effect from the “B” level simulation.

FIG. 80I (trace 6) illustrates xAB0 mode, wherein “x” number of breathsare stimulated at level “A,” followed by a breath stimulated at level“B,” followed by an unstimulated breath, (e.g. A is 2.0 mA and B is 1.8mA). The illustration shows x equals 3 (3AB0), although x may be anynumber of breaths (e.g., 3, 5, 7).

FIG. 80I (trace 7) illustrates xA0B mode, wherein “x” number of breathsare stimulated at level “A,” followed by an unstimulated breath,followed by a breath stimulated at level “B,” (e.g. A is 2.0 mA and B is1.8 mA). The illustration shows x equals 3 (3A0B), although x may be anynumber of breaths (e.g., 3, 5, 7

FIG. 80I (trace 8) illustrates xAB mode, wherein “x” number of breathsare stimulated at level “A,” followed by a breath stimulated at level“B,” (e.g. A is 2.0 mA and B is 1.8 mA). The illustration shows x equals4 (4AB), although x may be any number of breaths (e.g., 4, 6, 8).

Stimulation may also be delivered in two modes which are not inspiratorysynchronous: manual stimulation and asynchronous (fixed) stimulation.Manual mode delivers stimulation at any frequency, pulse width,amplitude, pulse configuration, and/or duration (e.g., up to 12seconds). In manual mode, stimulation is delivered by manually enteringa command via the programmer system to initiate delivery of astimulation burst or bursts. The stimulation continues until the burstduration expires or stimulation stop is commanded via the programmersystem. Manually delivered stimulations may be delivered in anyavailable pulse configuration.

Asynchronous mode (fixed mode) is when stimulation is delivered atregular programmable intervals (e.g., 2.5 seconds of stimulation,followed by 2.5 seconds off). The intervals may be set to a rate similarto a respiratory cycle, (e.g. 5 seconds). Alternatively, longerintervals (e.g. 8 seconds) may decrease the probability of missing twoconsecutive inspirations, and increase the probability of providing thepatient with stimulation during an entire respiratory cycle. This may beused during daytime familiarization, ensuring that the patient receivesstimulation in a regular fashion, as breathing patterns duringwakefulness may be more irregular and difficult to predict than duringsleep. In addition, this mode may be used to test the benefits ofasynchronous stimulation compared to inspiratory synchronousstimulation. Asynchronous stimulation may be initiated by programmingthe device to fixed mode and starting a therapy session. Fixed modestimulations may be in any available pulse train configuration.

Typically, stimulation is delivered during a therapy session having astart and a stop time. The patient or physician may start a therapysession using the therapy controller 2500 or programmer system 2100.Additionally, a therapy session may begin according to a programmableschedule. During a session, the start of stimulation may be delayed by aprogrammable delay, subject to patient preference. The patient orphysician may stop a therapy session using therapy controller 2500 orprogrammer system 2100. Additionally, a therapy session may stopaccording to a programmable schedule or programmable maximum sessionduration.

A patient or physician may also pause a therapy session for aprogrammable time using the therapy controller 2500 or programmer system2100. This pause function may be programmed to turn stimulation off orreduce the stimulation intensity. The pause function may be programmedto smart pause, wherein the stimulation level is automatically reducedafter a programmable number of pauses (e.g. after the second pause) in aprogrammable time period or session. Additionally, the smart pause mayincrease pause duration after a programmable number of pauses (e.g. thefirst pause is five minutes, the second pause is ten minutes). Thesepause functions, including smart pause, may allow a patient to reducestimulation for brief periods following an arousal from sleep.

At the start of a therapy session or following an interruption intherapy such as a pause, stimulation level may increase incrementallyfrom an initial stimulation level to an initial therapy level during aramping period. The ramp may occur over a programmable number ofstimulations, breaths, or time period. This ramp may also occur after apause or a motion event. The ramping feature may be more comfortable,allowing the patient to fall asleep more easily with the stimulation onor reduce the likelihood of causing arousal from sleep.

A patient may be able to tolerate more intense stimulation as a therapysession progresses. This higher intensity stimulation may provideenhanced therapy efficacy. The INS 1100 may be programmed to changestimulation level (e.g., amplitude or pulse width) during a therapysession from an initial level to a second, possibly more efficaciouslevel. This therapy stimulation configuration is illustrated in FIG. 80Jand is called core hours. This intensity change may occur after aprogrammable interval, for example after a fixed duration of time,number of breaths or stimulations (e.g., stimulation at 1.8 mA for thefirst hour of a therapy session, after which stimulation is increased to2.0 mA). This feature and the related parameters may be programmed by aphysician, for example based on patient feedback. This feature may allowa patient to fall asleep at a more tolerable level of stimulation, andthen as the therapy session progresses, receive more appropriatetherapeutic benefit.

Stimulation may be delivered during a therapy session, which may startand stop according to a programmable schedule or manual use of thetherapy controller 2500. The therapy controller 2500 may also allow thepatient to pause or adjust therapy settings. Summary history data fromeach session may be saved in the device memory. Data recorded mayinclude: start, pause, and stop times of the therapy session, scheduledor manual starts/stops, motion detector outputs, cycling detectoroutputs, prediction algorithm outputs, respiration timing, signalstability outputs, accelerometer outputs, impedance data from STL 1300and RSL 1200, number of breaths, number of stimulations in a session,average and median P-P sensing impedance (“Z”) amplitude values,stimulation settings and changes in stimulation settings such as corehours, pulse configuration, and ramping. These summary data allow aphysician or caretaker to understand how the patient is using thedevice, tolerating the stimulation, troubleshoot errors in programming,and estimate the therapeutic effects of the neurostimulator. Thisfeedback data may aid in determining if adjustments are needed to thepatient's therapy (e.g. patient is ready for stimulation up-titration).

Programmer System

As shown schematically in FIG. 65A, the programmer system 2100 includesa computer 2300, a programmer interface 2400, a programmer head 22000,and a sleep wand 27000. The programmer interface 2400 and programmerhead 22000 are similar in certain aspects to commercially availableprogrammers, which may be obtained from suitable manufacturers such asCCC Medical Devices (Montevideo, Uruguay). The programmer head 22000 isconnected to the programmer interface 2400 via a flexible cable 2210,and the programmer interface 2400 is connected to the computer 2300 viaa USB cable 2310. Cable 2210 may be coiled as shown or straight. Asshown in FIG. 85, the sleep wand 27000 may comprise a sleep wand head2720, a flexible cable 2710, and an LED 2730. The sleep wand 27000 mayconnect to the programmer interface 2400 via a flexible cable 2710. Thesleep wand head 2720 may be 3.2 inches in length, 2.1 inches in width,and 0.5 inches deep. The programmer system 2100 wirelessly communicateswith the INS 1100 via a wireless telemetry link (e.g., 30 KHz) utilizingan antenna and associated circuitry in the programmer head 22000. Theprogrammer may use long range telemetry such that the programmer head22000 may rest beside the patient without interfering with sleep. Theprogrammer interface 2400 provides analog to digital conversion andsignal processing circuitry allowing the computer 2300 to control andprogram the INS 1100 via the programmer head 22000. The programmer headincludes a power indication LED 2220, a signal strength LED array 2230(signal strength to/from INS 1100), an interrogate button 2240 (toupload data from INS 1100), a program button 2250 (to downloaddata/commands to the INS 1100) and a therapy-off button 2260 (to stoptherapy/stimulation output from the INS 1100). The computer 2300 maycomprise a conventional laptop computer with software to facilitateadjustment of a variety of INS 1100 parameters, including, for example:stimulation parameters (stimulation pulse amplitude, stimulation pulsefrequency, stimulation pulse width, stimulation duty cycle, etc.);respiration sensing algorithm parameters; stimulationtrigger/synchronization algorithm parameters, therapy delivery schedule,and various test functions. The sleep wand 27000 functions like theprogrammer head 22000, but is reduced in size for patient comfort duringsleep. There may be one LED 2730 to indicate signal presence. Frequencyof LED light pulses may indicate signal strength. The sleep wand 27000may exclude functional buttons (i.e. interrogate command, programcommand, and stop therapy command) found on the programmer head 22000.

With reference to FIG. 65B, a block diagram of example circuits2420/2270 for the programmer interface 2400 and the programmer head22000 are shown schematically. The programmer interface circuit 2420 iscontrolled by a microprocessor having a standard set of peripherals(RAM, flash, digital I/O, timers, serial ports, A/D converter, etc.).The microprocessor communicates with a standard personal computer (PC)2300 through a Universal Serial Bus (USB) interface. Commands and dataare passed from the computer 2300 to/from the microprocessor via the USBinterface and cable 2310. The USB interface also provides DC power forthe programmer interface circuit 2420 and the programmer head circuit2270 via cable 2210. The microprocessor controls the cable interfaceleading to the programmer head circuit 2270 via cable 2210. Theprogrammer head circuit 2270 contains telemetry driver and receiverelectronics that interface to the telemetry coil. The telemetry coil isdesigned to inductively couple signals from the programmer head circuit2270 to the coil in the INS circuit 1130 when the programmer head 22000is placed over the INS 1100 with the coils aligned. As an alternative totelemetry coils and an inductive link, RF antennae with associatedcircuitry may be used to establish a RF link to provide for arms-lengthtelemetry. The programmer head circuit 2270 also contains electronicsthat monitor the signal strength as received from the INS 1100. Theoutputs of the signal strength electronics drive display LED's for theuser. Another LED indicates that power is available, for example,supplied by the computer 2300. The programmer interface microprocessorcontrols and receives analog input signals from an isolated sensorinterface. The power and ground for the sensor interface are derivedfrom the USB power input, but provide DC isolation for this circuitry toprevent leakage currents from flowing through any patient connectionsthat may be present at the sensor inputs. The sensor inputs may beprotected against external high voltages (i.e. defibrillationprotection). The sensor input signals are amplified and filteredappropriately for the sensor type. The amplifier gain and filtercharacteristics may be controlled by microprocessor. The signals to/fromthe amplifier circuit are DC isolated to prevent leakage currents fromflowing through any patient connections that may be present at thesensor inputs. The sensor signals are digitized by the microprocessorand are transmitted through the USB link to the PC along with thetelemetered signals from the INS 1100 for recording and display.

With reference to FIG. 65C, a block diagram of example circuit 2440 forthe marker box 2430 is shown schematically. Generally, marker box 2430and associated circuitry 2440 replace the D/A circuits and analogoutputs 2410 of programmer interface circuit 2420 shown in FIG. 65Bproviding for the alternative arrangement illustrated in FIG. 68B. Themarker box circuit 2440 is separately connected to a Universal SerialBus (USB) port of the programmer computer 2300 via a USB cable. The USBinterface also provides DC power for the marker box circuit 2440 via theUSB cable. The power and ground for the marker box circuit 2440 arederived from the USB power input, but provide DC isolation for thiscircuitry to prevent leakage currents from flowing through any equipmentthat may be connected to the patient. Analog marker output data signalsare transmitted from the PC 2300 to control the digital to analog (D/A)converter outputs. These analog output signals may be connected tostandard PSG recording equipment 2800. Signals from the INS 1100 (suchas sensed respiration impedance and stimulation output amplitude) can berepresented by these outputs to allow simultaneous recording with otherstandard PSG signals (flow, belts, EMG/ECG, etc). The programmer 2300may be enabled to automatically switch programmable settings at regulartime intervals, allowing respiratory sensing vectors, stimulationlevels, stimulation modes, or stimulation pulse configurations to bealtered at specified intervals during sleep. Sampled values may beselected such that only a limited number of settings are sampled.

As mentioned previously, the INS 1100 records session summary data. Theprogrammer computer 2300 may display these data using text and images tographically display device settings, session data, and analyses of data.This data may be used to evaluate system performance and guideprogramming of settings. The patient's name or identifier may be storedin the INS 1100 and/or displayed on the programmer computer 2300. Alltext and symbols displayed by the programmer 2300 may be in a variety ofselectable languages. The programmer 2300 may have the capability toconnect to the internet. Through this connection files may be uploadedto a database to enable remote real time monitoring of device operation,recorded data and settings. The connection may also be used to updatethe programmer application software and or the (indirectly) the INSfirmware.

The programmer 2300 may display and tag data to a variety of dates andtimes. These times may programmed to take into account daylight savingstime, local time, Greenwich Mean Time, or a free-running counter in theINS 1100.

The programmer 2300 may display the voltage (or other capacitymeasurements) of battery 1140. In addition, an elective replacementindicator (ERI) and end of life (EOL) indicator may be displayed on theprogrammer as the battery nears depletion. There may be several monthsfrom ERI to EOL or alternatively, two months from ERI to EOL, with anestimated one month of use after EOL.

Therapy Controller

As shown schematically in FIG. 66A, the therapy controller 2500 may beused by the patient to control limited aspects of therapy delivery. Thetherapy controller 2500 is similar in certain aspects to commerciallyavailable patient controllers, which may be obtained from suitablemanufacturers such as CCC Medical Devices (Montevideo, Uruguay). Thetherapy controller 2500 houses a battery, an antenna, and associatedcircuitry (not visible) to control limited aspects of therapy deliveryvia a wireless telemetry link (e.g., 30 KHz) with the INS 1100. Therapyis normally operated in a manual mode but may also be set for automaticdelivery according to a predefined schedule (set by physician using theprogrammer during titration). The therapy controller has a userinterface including start button 2510 (to start therapy delivery), astop button 2520 (to stop therapy delivery) and a pause button (to pausetherapy delivery or reduce stimulation intensity to a programmablevalue), each with associated LED indicators 2540 which flash when thecorresponding button is depressed and illuminate steadily when thecommand is received by the INS 1100. The buttons may be backlit whenpressed for ease of use at night. The user interface also includes aschedule set LED 2550 that illuminates if a therapy delivery schedulehas been programmed, and a contact physician LED 2560 that illuminatesin the event of a low battery or a malfunction requiring a physicianvisit. In addition, this light may illuminate at ERI or EOL time points.

The therapy controller may have additional functionality (e.g., morebuttons) which can be set to give the patient limited control overselect therapy settings. These settings include, but are not limited to,stimulation intensity (e.g., amplitude), stimulation mode, pulse trainconfiguration, core hours stimulation settings, ramp, programmableschedule, clock, and motion inhibit programmable values.

As mentioned previously, the INS 1100 contains data, including metricsfrom therapy sessions. The therapy controller 2500 may wirelesslycommunicate with the INS 1100 to download any data to the INS. This datamay be stored in internal memory or removable memory such as a USB flashdrive or smart card. This data may be uploaded (e.g. from the patient'shome computer) for the physician to read. This may allow the physicianto monitor device use, home efficacy, or the patient's acclimation.

An alternative embodiment of the user interface may include an LCDdisplay or a touchscreen. This allows for multiple functions to beintegrated into the therapy controller while keeping the interfacesimple. This may also allow for larger text.

With reference to FIG. 66B, a block diagram of an example circuit forthe therapy controller 2500 is shown schematically. The therapycontroller circuit 2570 includes a battery powered microprocessor havinga standard set of peripherals (RAM, flash, digital I/O, timers, serialports, A/D converter, etc.). The microprocessor operates in a low powermode to conserve battery power. The microprocessor controls thetelemetry driver and receiver electronics that interface with thetelemetry coil. The telemetry coil is designed to inductively couplesignals to the INS telemetry coil when aligned. The microprocessormonitors the membrane switches and reacts to switch closures byactivating display LED's and initiating telemetry commands to the INS.As an alternative to telemetry coils and an inductive link, RF antennaewith associated circuitry may be used to establish a RF link to providefor arms-length telemetry. After communicating with the INS, statusinformation can be displayed to the user. The microprocessor alsocontrols a beeper which can provide audio feedback to the user whenbuttons are pressed and to indicate the success or failure ofcommunications with the INS. The beeper may have a mute function orvolume control.

Magnet

As schematically shown in FIG. 67, an annular magnet 26000 may beprovided to the patient to deactivate or inhibit the INS 1100 in theevent the therapy controller 2500 is not available or functioning. Themagnet 26000 may comprise a permanent annular-shaped magnet made offerrite strontium material coated with epoxy. The magnet 26000 mayproduce a strong field of 90 Gauss at 1.5 inches from the surface of themagnet along the centerline of the hole. The magnet 26000 may be used(or carried by) the patient in case of emergency. When temporarily (2seconds or more) placed over the implanted INS 1100 on the skin orclothing, the magnet 26000 disables current and future therapy sessions.Although therapy sessions are disabled by the magnet 26000, all otherfunctions of the INS 1100 may remain enabled including telemetrycommunication with the programmer system 2100 and therapy controller2500. Therapy sessions may be re-enabled using the programmer system2100. The therapy controller 2500 may also re-enable therapy sessions ifthe therapy controller 2500 has been authorized by the programmer system2100 to do so. Therapy sessions may be re-enabled using the therapycontroller 2500 by initiating a new therapy session. Alternatively, thetherapy may be temporarily inhibited during placement of the magnet. Ifleft in place for a specified time period (e.g. one minute), therapy maybe deactivated.

Interface with PSG Equipment

The programmer interface 2400 may include an input/output (I/O) link2410 to allow connection to polysomnographic (PSG) equipment 2800 asschematically shown in FIG. 68A. Typical PSG equipment 2800 includes acomputer 2810 connected to a plurality of sensors (e.g., airflow sensor2820, respiratory effort belts 2830) via interface hardware 2840. TheI/O link 2410 may be used in a number of different ways. For example,analog data signals from the PSG equipment 2800 may be downloaded to thecomputer 2300 of the programmer system 2100 to record and/or display PSGdata (e.g. airflow) together with therapy data. Alternatively or inaddition, digital data signals from the INS 1100 and/or the programmersystem 2100 may be uploaded to the computer 2810 of the PSG equipment2800 to record and/or display therapy data (e.g., stimulation amplitude,stimulation pulse width, and/or respiration data such as bio-impedance,vector, filter settings, prediction markers, or accelerometer data)together with PSG data. The circuitry corresponding to I/O link 2410 maybe incorporated into the programmer interface 2400 as shown in FIG. 68A,or may be incorporated into a separate marker box 2430 as shown in FIG.68B.

Synchronizing data from the sensors 2820/2830 of the PSG equipment 2800with data from the INS 1100 via the programmer system 2100 may bebeneficial to facilitate therapy titration and efficacy measurement.Although the programmer system 2100 and the PSG equipment 2800 may bedirectly connected by I/O link 2410, transmission delay in each systemmay result in asynchrony. Data synchronization between the systems maybe addressed in a number of different ways. For example, if the delaysin each system are relatively fixed and below an acceptable threshold(e.g., 0.5 to 1.0 second), no synchronization step need be taken. If thedelays in each system are relatively fixed but above an acceptablethreshold (e.g., above 0.5 to 1.0 second), data from the system withless delay may be offset (delayed) by a fixed time value to align withdata from the system with more delay. As an alternative, a timing signal(e.g., from a clock signal generator separate from or integral with oneof the systems) may be input into the PSG equipment 2800 and programmersystem 2100 to allow time stamped data independently collected by eachsystem to be merged and synchronized by post processing.

Treatment Overview

FIG. 69A schematically illustrates the incision sites (solid thicklines) and tunneling paths (dotted lines) for implanting the INS 1100,STL 1300 and RSLs 1200. The implant procedure may be performed by asurgeon (e.g., otolaryngologist) in a 1-2 hour surgical procedure withthe patient under general anesthesia, for example. In general, theimplant procedure involves placing the cuff 1350 of the STL 1300 on thehypoglossal nerve via a submandibular dissection, and tunneling the leadbody 1330 and sigmoid section 1370 of the STL 1300 subcutaneously downthe neck to the INS 1100 in a subcutaneous pocket in the infraclavicularregion. From the infraclavicular pocket, the RSLs 1200 may be tunneledsubcutaneously toward midline and then laterally along the costalmargins.

After a healing period of a few weeks, the patient returns to the sleeplab where a sleep technician, under the supervision of a certified sleepphysician (e.g., pulmonologist), uses the programmer system 2100 toprogram the INS 1100 (e.g., set the therapy delivery schedule andtitrate the stimulus to optimize efficacy during sleep).

Immediately after the titration visit, the patient may return home andbegin use. A therapy delivery session may begin according to thepre-defined therapy delivery schedule, which may be set to coincide withwhen the patient normally goes to sleep. At the beginning of a therapydelivery session, stimulus may be delayed for a period of time to allowthe patient to fall asleep. The therapy delivery session may endaccording to the pre-defined therapy delivery schedule, which may be setto coincide with when the patient normally wakes up. The therapydelivery session may be programmed to not exceed eight hours. Thepatient can use the therapy controller 2500 to adjust limited aspects oftherapy delivery. For example, the patient can use the therapycontroller 2500 to stop, pause and restart a scheduled therapy session.In addition, the therapy controller 2500 can be used to manually controltherapy delivery rather than operate according to a preset schedule.This may be beneficial when the patient has an irregular sleep schedule,for example. In this mode, the therapy controller 2500 can be used bythe patient to manually start, stop, and pause a therapy session.

Surgical Implant Procedure

With continued reference to FIG. 69A, the internal components 1000 maybe implanted using the following surgical procedure, which is given byway of example, not limitation. Unless specifically stated, the order ofthe steps may be altered as deemed appropriate. Although the INS 1100may be surgically implanted on the right or left side, the right side ispreferred to leave the left side available for implantation of cardiacdevices that are traditionally implanted on the left side. The rightside is also preferred for the RSL 1200 (if one RSL is used) to providea clean respiratory signal that is less susceptible to cardiac artifactthan the left side.

Standard surgical instruments may be used for incisions, dissections,and formation of subcutaneous pockets. Commercially available nervedissection instruments may be preferred for dissecting the hypoglossalnerve and placing the STL cuff 1350 on the nerve. A tunneling tool 3000,as schematically shown in FIGS. 69B and 69C, may be used for tunnelingthe STL 1300 and RSL 1200 leads. The tunneling tool (also referred to astunneler) 3000 includes a relatively rigid grasper 3010, a tubularsheath 3020, and a cap 3030. The sheath 3020 and cap 3030 are sized tobe slid over the grasper 3010. The cap 3030 may include a radiopaqueagent such as barium sulfate loaded at 18% by weight, for example. Thegrasper 3010 may be formed of stainless steel and includes a shaft 3012,distal jaws (similar to an alligator clip) 3014, and a proximal handle3016. The jaws 3014 are biased to the closed position and may be used tograsp the proximal end of the RSL 1200 or STL 1300 using the leadcarrier 3100 as protection. The lead carrier 3100 may comprise a smallpolymeric tube with an inside diameter sized to form an interference fitwith the proximal end of the RSL 1200 or STL 1330. The sheath 3020 maycomprise a polymeric tube with two open ends, and the cap 3030 maycomprise a polymeric tube with one open end and one closed end for bluntdissection. The proximal end of the cap 3030 may include a taperedsection to fit into the distal end of the sheath 3020 and form aninterference fit therewith. In the embodiment shown in FIGS. 69B and69C, the sheath 3020 may have an outside diameter of approximately 0.37inches and a length of about 10.9 inches. The cap may an outsidediameter tapering from approximately 0.37 inches and a length of about1.7 inches. The shaft 3012 may have a diameter of about 0.19 inches andtogether with the jaws 3014 may have a length sufficient to fill thelength of the sheath 3020 and cap 3030. The handle 3016 may have adiameter of about 0.5 inches and a length of about 3.0 inches.

An alternative tunneling tool 3000 is schematically shown in FIGS. 69Eand 69F may be used for tunneling the STL 1300 and RSL 1200. In thisembodiment, the tunneling tool 3000 includes a relatively rigid grasper3010, a tubular sheath 3020, and a cap 3030. The sheath 3020 and cap3030 are sized to be slid over the grasper 3010. The cap 3030 mayinclude a radiopaque agent such as barium sulfate loaded at 18% byweight, for example. The grasper 3010 may be formed of stainless steeland includes a shaft 3012, distal connector 3018, and a proximal handle3016. The connector 3018 includes threads that mate with correspondingthreads in the cap 3030. The connector 3018 may also include ring barbsthat form an interference fit with the inside of the lead carrier 3100for releasable connection thereto. The lead carrier 3100 may comprise asmall polymeric tube with an inside diameter sized to form aninterference fit with the proximal end of the RSL 1200 or STL 1330. Thesheath 3020 may comprise a polymeric tube with two open ends, and thecap 3030 may comprise a polymeric tube with one open end and one closedend for blunt dissection. The proximal end of the cap 3030 includesinternal threads to screw onto the connector 3018 and hold the sheath3020 on the shaft 3012. In the embodiment shown in FIGS. 69E and 69F,the sheath 3020 may have an outside diameter of approximately 0.28inches and a length of about 12.3 inches. The cap may an outsidediameter tapering from approximately 0.13 inches and a length of about1.0 inches. The shaft 3012 may have a diameter of about 0.22 inches andmay have a length sufficient to fill the length of the sheath 3020. Thehandle 3016 may have a diameter of about 0.5 inches and a length ofabout 3.74 inches.

The patient is prepared for surgery using conventional practiceincluding standard pre-operative care procedures, administration ofantibiotics as appropriate, and administration of steroids asappropriate to reduce swelling around the nerve dissection. Becausetongue movement must be observed during test stimulation, it isrecommended that no long-acting muscle relaxants be used during surgicalpreparation no muscle relaxants be used during implant. Generalanesthesia is administered according to conventional practice and thepatient is intubated using an endotracheal tube, taking care to positionthe endotracheal tube so that the tongue is free to protrude during teststimulation.

The neck is then extended to expose right submandibular region and asterile field is created around the neck and thorax, taking care toavoid obstructing visualization of the oral cavity (a clear steriledrape over the mouth may be used). By way of a neck incision (A), thehypoglossal nerve is then exposed deep to the submandibular gland.Because the INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing, this dissection isalso preferably performed on the right side. The branch of thehypoglossal nerve believed to innervate the genioglossus muscle is thenidentified and isolated. Confirmation of correct nerve location may beachieved by performing a test stimulation later in the procedure. Theidentified nerve branch is then circumferentially dissected toaccommodate the cuff 1350. The short side 1352 of the cuff 1350 isdesigned to reside on the deep side of the nerve, and the long side 1354of the cuff 1350 is designed to reside on the superficial side of thenerve.

The appropriate sized cuff 1350 is then selected based on the nervediameter at the intended location for cuff placement. Nerve size may beassessed using reference size (e.g., forceps of know width), a caliper,or a flexible gauge that wraps around the nerve, for example. The cuff1350 is then opened and placed around the nerve. The strap 1356 on thecuff 1350 may be used to facilitate placement of the cuff 1350 aroundthe nerve. A curved forceps may be placed under the nerve to grasp thestrap 1356 and gently pull the cuff 1350 onto the nerve. The strap 1356is then placed through the loop (buckle) 1358 on the cuff 1350. The cuff1350 may be available in two sizes (small and large), and the small cuffmay have an indicator mark (not shown) on the strap 1356 that should bevisible after insertion through the loop 1358. If the indicator mark isnot visible, the small cuff may be too small and should be replaced witha large cuff. The surgeon then verifies that the cuff 1350 is notpulling or twisting the nerve, and that there is contact between theinside of the cuff 1350 and the nerve.

A test stimulation is then performed to confirm correct positioning ofthe cuff 1350 on the nerve. To conduct a test stimulation, the proximalend of STL 1300 is plugged into the INS 1100 and the programmer system2100 is used to initiate a test stimulation signal delivered from theINS 1100 to the nerve via the STL 1300. The test stimulation isperformed while observing, for example, tongue movement by direct visualobservation, airway caliber by nasal endoscopy, lateralfluoroscopy/cephalogram, etc. Correct placement of the cuff on the nervemay be confirmed by, for example, observing tongue protrusion, anincrease in retro-glossal airway caliber, an increase in retro-palatalairway caliber, an increase in stiffness of the anterior and/or lateralwalls of the retro-glossal airway with or without an increase in airwaycaliber, anterior movement with or without inferior movement of thehyoid bone, among others. Incorrect placement of the cuff on the nerveis indicated, for example, when the tongue is observed to retract(posterior movement), a decrease in retro-glossal airway caliber, adecrease in retro-palatal airway caliber, superior movement andparticularly unilateral superior movement of the hyoid bone, amongothers. If necessary, the cuff 1350 may be repositioned at a differentlocation along the length of the nerve to obtain the desired effect. Thecapture threshold and impedance values are recorded and the STL 1300 isdisconnected from the INS 1100. A fascial wrap is then sutured over thecuff on the superficial side of the nerve.

A strain relief loop (L) in the STL 1300 is then created by arrangingapproximately 6 cm of the STL sigmoid body 1370 in a C-shape inside asmall subcutaneous pocket formed via the neck incision (A) by bluntdissection superficially along the lateral surface of the digastricmuscle in a posterior direction.

A pocket for the INS 1100 is then created by making an incision (B) downto the pectoralis fascia up to 2 finger breadths below the rightclavicle. The INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing. Blunt dissectioninferior to the incision is used to create a pocket large enough to holdthe INS 1100. The pocket should be inferior to the incision (B) suchthat the incision (B) does not reside over the INS 1100 when laterplaced in the pocket.

A tunnel is formed for the STL 1300 using the tunneler 3000 (sheath 3020and cap 3030 placed over grasper 3010) to tunnel along a path (C) fromthe infraclavicular INS pocket to the neck incision (A). As shown inFIG. 69C, the lead carrier 3100 is then placed on the most proximalelectrical contact of the STL proximal connector 1310. The cap 3030 isremoved from the sheath 3020 to expose the jaws 3014 of the grasper 3010and grab the lead carrier 3100. While holding the sheath 3020 in place,the grasper 3010 is pulled proximally to pull back the STL 1300 throughthe sheath 3020, taking care not to pull out the C-shaped strain reliefor disturb the cuff. If the C-shaped strain relief loop (L) is pulledout, it should be replaced into the small pocket. The grasper 3010 isreleased from the lead carrier 3100 and the lead carrier 3100 is removedfrom the STL 1300. The sheath 3020 is then removed from the body leavingthe STL 1300 in place. The neck incision (A) need not be closed at thistime, but rather may be closed later in the procedure allowingconfirmation that the C-shaped strain relief remains in the smallpocket.

The right RSL 1200 is placed near the right costal margin by making twosmall incisions (D and E) as shown. The medial incision (D) may be madeapproximately 40% (+/−5%) of the distance from the midline to themidaxillary line, and approximately two finger breadths superior to thecostal margin. The lateral incision (E) may be made approximatelyhalfway between the medial incision (D) and the midaxillary line (i.e.,extending from the medial incision (D), approximately 30% (+/−5%) of thedistance from the midline to the midaxillary line), and approximately upto two finger breadths superior to the costal margin. Using the tunneler3000 (sheath 3020 and cap 3030 placed over grasper 3010), a tunnel (F)is formed from the medial incision (D) to the posterolateral incision(E). The lead carrier 3100 is then placed on the most proximalelectrical contact of the RSL 1200 proximal connector 1210. The cap 3100is then removed from the sheath 3020 to expose the jaws 3014 of thegrasper 3010 and grab the lead carrier 3100. While holding the sheath3020 in place, the grasper 3010 is pulled proximally to pull back theRSL 1200 through the sheath 3020. The grasper 3010 is released from thelead carrier 3100 and the lead carrier 3100 is removed from the RSL1200. The sheath 3020 is then removed from the body leaving the RSL 1200in place. Each suture tab 1270 is secured to the underlying tissue bydissecting down to the muscle fascia adjacent the anchor tabs 1270 onthe RSL 1200 and suturing each anchor tab 1270 to the muscle fascia.Permanent sutures are recommended to avoid movement of the RSL 1200before tissue encapsulation, and braided suture material is recommendedfor knot retention. The left RSL 1200 is then implanted along the leftcostal margin in the same manner as described above.

The right RSL 1200 is then tunneled to the pocket (B) for the INS 1100.Using the tunneler 3000 (sheath 3020 and cap 3030 placed over grasper3010), a tunnel (G) is formed from the infraclavicular pocket to themedial incision (D). The lead carrier 3100 is placed on the mostproximal electrical contact of the RSL 1200 proximal connector 1210. Thecap 3030 is then removed from the sheath 3020 to expose the jaws 3014 ofthe grasper 3010 and grab the lead carrier 3100. While holding thesheath 3020 in place, the grasper 3010 is pulled proximally to pull backthe RSL 1200 through the sheath 3020. The grasper 3010 is released fromthe lead carrier 3100 and the lead carrier 3100 is removed from the RSL1200. The sheath 3020 is then removed from the body leaving the RSL 1200in place. The left RSL 1200 is then tunneled to the pocket for the INS1100 in the same manner as described above.

The STL 1300 and RSLs 1200 are then connected to the INS 1100. Since oneSTL port is not used in this example, a port plug (small siliconecylinder) is inserted into header port STL-2. The RSLs 1200 are pluggedinto ports RSL-A and RSL-B, the STL 1200 is plugged into port STL-1 andthe set screws are tightened to 1 click using a torque wrench.

A closed loop test may be performed to confirm proper operation byobservation of tongue protrusion in concert with inspiration. The INS1100 and proximal portions of the leads 1200/1300 are then placed intothe infraclavicular pocket, looping the excess lead length beneath oraround the INS 1100. Care should be taken not to pull out the C-shapedstrain relief loop (L) in the STL sigmoid lead body 1370 whilemanipulating the INS 1100 into place. The INS 1100 is then sutured tounderlying fascia through both suture holes found in the header 1110 ofthe INS 1100. Permanent sutures are recommended for to avoid movement ofthe INS before tissue encapsulation, and braided suture material isrecommended for knot retention. Another system test may be performed atthis point. After confirming that the C-shaped strain relief loop (L) ispresent in small pocket at neck incision, the incisions may be irrigated(optionally with an antibiotic solution) and closed using conventionaltechniques. After a healing period of approximately one month, thepatient may undergo a sleep study to confirm proper operation of thesystem and to titrate therapy.

An alternative lead routing schematic is shown in FIG. 69D. In thisalternative embodiment, the left and right lateral incision sites E arelocated 80% of the distance from the midline to the mid-axillary line,up to two finger breadths above the rib costal margin. The medialincision sites D are then located a straight line distance of 9.5 cmmedial, up to two finger breadths above the rib costal margin.

Screening Methods

As schematically shown in FIG. 70, an external system may be used toconduct a stimulation screening session prior to full implantationwherein the genioglossus muscle (innervated by the hypoglossal nerve) isstimulated with fine wire electrodes (FWEs) 2860 inserted submentallywith a needle during an otherwise conventional sleep (PSG) studyutilizing PSG equipment 2800. The FWEs 2860 may be inserted into thegenioglossus under the guidance of ultrasound. Stimulation signals maybe delivered to the genioglossus muscle by connecting the FWE's 2860 toan external stimulator and switch box 2870. The external stimulator andswitch box 2870 may comprise the INS 1100, programmer head 22000 andprogrammer interface 2400 in a common housing, with the stimulationoutput of the INS 1100 connected to the FWEs 2860 and the sensing inputof the INS 1100 connected to skin surface electrodes 2890 forbio-impedance respiration measurement. A stimulation marker outputsignal 2872 from the external stimulator and switch box 2870 to the PSGequipment 2800 allows stimulation and/or respiration data to besynchronized and merged with PSG data in near real time. The externalstimulator and switch box 2870 may include a manually operated switcharray to select a single FWE or a combination of FWEs 2860 to deliver astimulation signal to the genioglossus muscle. With this arrangement,stimulation may be delivered via FWEs 2860 automatically triggered byinspiration measured via skin surface electrodes 2890 or manuallytriggered via activating a manual trigger switch 2880. The efficacy ofdelivering stimulus to the genioglossus muscle may be observed andmeasured using conventional PSG parameters. Efficacious results may beindicated by a significant reduction in apnea hypopnea index, anincrease in flow, a decrease in critical closing pressure, and/or anincrease in airway caliber, for example. Patients that respondadequately to stimulation during the trialing period (“responder”) mayreceive the implanted device. Perhaps more importantly, patients that donot adequately respond to stimulation during the trialing period(“non-responder”) would not receive the implanted device.

As schematically shown in FIG. 71, an external system may be used toconduct a respiration screening session prior to full implantationwherein skin surface electrodes are placed on the skin at or near thelocations that the respiration sensing electrodes and INS would beimplanted. Bio-impedance measurements may be taken during a sleep studyto determine if an adequate bio-impedance signal may be obtained. Inaddition, different locations for the skin surface electrodes may betested to determine the optimal locations for the respiration sensingelectrodes during implantation.

The stimulation trialing period and the respiration trialing period maybe combined into a single study, wherein skin surface bio-impedancemeasurements may be used to provide closed-loop feedback for stimulatingsynchronous with inspiration. Patients would then be categorized asresponders or non-responders depending on the outcome of the closed-loopstudy.

Titrating Methods

As described previously, after implantation and a healing period ofapproximately one month, the patient may undergo a sleep (PSG) study toconfirm proper operation of the system and to titrate therapy. Titrationmay utilize the set-up illustrated in FIG. 68, wherein the programmersystem 2100 interfaces with the PSG equipment 2800. Titration generallyinvolves (1) selecting an optimal respiratory sensing signal and (2)selecting optimal stimulation signal parameters (e.g., stimulationintensity, respiratory phase adjustment). After titration, therapyefficacy may be measured using standard PSG techniques. For example: arespiratory sensing vector may be selected based on signal strength andstability, reliability; the stimulation amplitude may be selected basedon maximum airflow; the phase adjustment may be selected based onstimulation alignment with inspiratory airflow; and therapy efficacy maybe evaluated based on elimination of indicia of sleep disorderedbreathing such as AHI.

Selecting an optimal respiratory sensing signal involves selecting thebest vector defined by two sets of electrodes on the RSL or one set ofelectrodes on the RSL and the housing of the INS. Selection may be basedon maximum signal strength, consistent correlation to inspiration, andmaximum signal stability/reliability across sleep stages, bodypositions, and disordered breathing events, for example. A stable signalhas a minimum probability of signal inversion. A reliable signal has aminimum probability of signal loss, and therefore may preferably have aminimum threshold of 0.2 to 0.5 Ohms peak-to-peak, for example. Theoptimal vector may be selected by incrementally scrolling through all ora preferred subset of possible vectors while sampling the respirationsignal and comparing the signal against themselves or predefinedthresholds. This scrolling technique may be performed manually (withinputs via the programmer system) or automatically (i.e., programmed).The sampling technique may also be performed manually (visualobservation using programmer system) or automatically (i.e.,programmed). For practical purposes, the respiration sensing vector maybe evaluated while the patient is awake by having the patient assumedifferent body positions while at resting respiration. Alternatively,the respiration sensing vector may be evaluated while the patient isasleep during different stages of sleep and during different sleepdisordered breathing events. The INS is capable of streaming out datafrom two or more sensing vectors which allows simultaneous comparison.This may be especially useful during titration (body position testingand during sleep study) to minimize chance that evaluation of a givenvector is biased by events unrelated to a given vector.

Selecting optimal stimulation signal parameters (e.g., pulse amplitude,pulse frequency, pulse width, duty cycle, phase adjust, etc.) tooptimize efficacy (e.g., as measured by apnea index, hypopnea index,respiratory disturbance index, apnea-hypopnea index, and otherobstructive sleep apnea efficacy measures) is preferably performed whilethe patient is sleeping.

The adjustable stimulation parameters include pulse frequency (range of20 to 50 Hz, nominal 40 Hz), pulse width (range of 30 to 215.mu.s,nominal 90.mu.s), pulse amplitude (range of 0.4 to 5.0 mA, nominal 0.4mA), duty cycle (range of 41% to 69%, nominal 50%), and phase adjust(range of −1.5 to +0.5 s, nominal −0.5 s). In general, during thestimulation titration process, it is preferable to begin with the lowestsettings for pulse width (30.mu.s) and amplitude (0.4 mA) at a nominalfrequency (40 Hz). If stimulation produces pulsatile (vibrating)contractions, the frequency may be increased to 50 Hz. The pulse widthis incrementally increased to 60.mu.s, then to nominal (90.mu.s),keeping Amplitude at 0.4 mA. With the pulse width set to 90.mu.s,amplitude may be iterated according to the process describedhereinafter. If maximum amplitude is reached and additional intensity isrequired, the pulse width may be increased while reducing amplitude tominimum (0.4 mA). If maximum pulse width (215.mu.s) is reached andadditional intensity is required, frequency may be increased whilereducing the pulse width to 90.mu.s and the amplitude to minimum (0.4mA).

An initial step in titrating may involve defining a stimulationoperating window, preferably while the patient is awake, defined at itslower limit by a capture threshold and at its upper limit by a comfortthreshold. The capture threshold may be defined as the stimulation levelat which some indication of a potentially beneficial effect (e.g., grosstongue movement or stiffening) is observed. The comfort threshold may bedefined as the stimulation level at which the patient experiences anunacceptable sensation (e.g., pain) while awake or at which the patientpartially or completely arouses (e.g., lighter stage of sleep or awake)during sleep. Human subjects have been observed to tolerate (i.e., notarouse) higher stimulation intensities while asleep than they couldtolerate while awake. The operating window may be determined at thebeginning of the titration sleep study (e.g. during set-up when thepatient is awake) to help determine a lower limit or starting point forstimulation (capture threshold) and an upper limit or ending point forstimulation (comfort threshold), between which the stimulation level maybe adjusted (e.g., increased) until an efficacious level is found.

Using the programmer system 2100 to set the stimulation parameters, thestimulation level may be initially set at the lower limit or apercentage (e.g., 50%) of the upper limit, followed by a monitoringperiod where efficacy is measured using standard PSG techniques. Afterthe initial monitoring period, the stimulation level may beincrementally increased, followed by another monitoring period. This maycontinue in a step-wise fashion up to the upper limit for stimulation oruntil no significant difference in measured efficacy is discernablebetween stimulation levels. If no significant difference in measuredefficacy is discernable between a lower and higher stimulation level,the lower level may be selected as the desired stimulation dose.

Because efficacy measures (e.g., apnea-hypopnea index) typically takehours to collect, it may be desirable to create a controlled,flow-limited condition and measure a surrogate parameter (e.g., airflow,critical closing pressure, etc.) in order to complete the step-wisetitration process in a reasonable amount of time (e.g., a single or halfnight sleep study). In addition, because a number of sleep conditions(e.g., sleep stage) change over the course of an all night study, it isbeneficial to titrate therapy over a shorter period of time during whichsleep conditions are less likely to change as significantly. To create aflow-limited state, the patient may be fitted with a CPAP (continuouspositive airway pressure) device comprising a blower connected via ahose to a mask (incorporating a airflow meter such as apneumotachometer) placed over the patient's nose and/or mouth. The CPAPdevice may have the capability to deliver variable pressure down toapproximately 0 cm H₂O or lower, in increments of 0.10 cm H₂O or less,for example. Such a CPAP device is also called a P_(crit) device for itsability to assist in making critical closing pressure measurements ofthe upper airway using techniques developed by Schwartz et al. Theairway in people with obstructive sleep apnea will partially orcompletely occlude during sleep in the absence of adequate positiveairway pressure. Thus, adjusting the CPAP pressure below the therapeuticlevel for a given patient will create a controlled flow-limitedcondition. Using these techniques, the stimulation intensity level(e.g., current, mA) or other stimulation parameter (e.g., pulsefrequency, pulse duration, phase adjustment, etc.) may be titrated byprogressively creating greater flow restriction while determining if achange (e.g., an increase) in a stimulation parameter (e.g., intensity)results in an increase in flow.

With reference to FIGS. 72A and 72B, stimulation may be delivered atdifferent levels, different sequences, and different modes duringtitration. These stimulation alternatives may also be used for therapydelivery, if desired. In FIG. 72, each burst of stimulation is shown asa positive square wave and corresponds to a train of pulses as describedpreviously. The bottom trace #7 in FIGS. 72A and 72B correspond to arespiratory flow signal wherein the negative portion of the tracecorresponds to inspiration, and the positive portion of the tracecorresponds to expiration.

As shown in FIGS. 72A and 72B, stimulation bursts may be delivered atdifferent levels and in different sequences. For example, thestimulation burst may be programmed to be “A or B” (traces #1, #4 and#8), where stimulation is delivered at level “A” until commanded todeliver at level “B”, or delivered at level “B” until commanded todeliver at level “A”. Stimulation level “A” may correspond to a firstselected level and stimulation level “B” may correspond to a secondselected level, wherein the first level “A” is different than the secondlevel “B” in terms of amplitude, pulse width and/or duration.Alternatively, the stimulation burst may be programmed to be “nested”(traces #2 and #3), where the stimulation burst comprises a composite oflevels “A” and “B”. As a further alternative, the stimulation burst maybe programmed to “toggle” (traces #5 and #6) between the same ordifferent level in a repeating pattern (e.g., “AB”, “ABAB”, “0A0B”,“AA”, etc.).

Also as shown in FIG. 72, stimulation may be delivered in three basicmodes: manual synchronized; inspiratory synchronized; and triggered.Traces #1 and #2 illustrate manually synchronized stimulation delivery,wherein stimulation is delivered by manually entering a command via theprogrammer system to initiate stimulation delivery of each burst (e.g.,when the user observes or anticipates inspiration on PSG, the usermanually enters a command to initiate stimulation delivery). Traces #3,#4, #5 and #8 illustrate inspiratory synchronized stimulation delivery,wherein stimulation is automatically delivered according to an algorithmthat predicts the inspiratory phase and initiates stimulation deliveryat a desired time relative to inspiration such as at or just prior toinspiratory onset. Trace #6 illustrates triggered stimulation delivery,wherein each stimulation burst is initiated and terminated by a fiducialof the respiratory signal (e.g., positive peak, negative peak,cross-over point, etc.) which may or may not correspond to aphysiological event (e.g., inspiratory onset), and which may or may notincorporate a fixed delay. Thus, in triggered mode, the stimulationburst is initiated by a fiducial and terminated by the next occurrenceof the same fiducial in a repeating pattern.

The manually-synchronized A or B mode (trace #1) allows the user toprogram stimulation parameters for two (A & B) separately deliverablestimulation bursts. On user command, a single burst of stimulation isdelivered almost immediately corresponding to A's settings, likewise forB. A and B can be defined with unique amplitudes, pulse widths, anddurations; but with a common frequency. The dots on trace #1 indicatethe time of manual command followed by the delivery of stimulationimmediately thereafter.

The manually-synchronized nested burst (trace #2) allows the user toprogram stimulation parameters for a nested stimulation burst. On usercommand, a single burst of stimulation is delivered almost immediatelycorresponding to the nested burst parameters. The user defines thenested burst parameter by programming stimulation parameters for aprimary mode and separately for a secondary mode. The secondary mode isof shorter duration than the primary mode. The secondary mode may becentered on the primary mode as shown, or shifted to the beginning orend of the primary mode. The two modes can be defined with uniqueamplitudes, pulse widths, and durations; but with a common frequency.The dots on trace #2 indicate the time of command followed by thedelivery of stimulation immediately thereafter.

The inspiratory-synchronous nested mode (trace #3) delivers stimulationbursts synchronous with inspiration as determined by device and therapydelivery algorithm settings and sensed respiratory signal. This mode issimilar in function to manually-synchronous nested mode (trace #2) withthe following three differences: first, after user command thestimulation burst does not begin immediately but instead is deliveredduring the next inspiration as predicted by the therapy deliveryalgorithm; second, the duration of the stimulation burst is notprogrammed but is instead determined by the therapy delivery algorithm;and third, the nested stimulation burst will continue to be delivered onevery respiratory cycle until stopped. The lines below trace #3 indicatethe time window during which a command will cause therapy to begin onthe following inspiration.

The inspiratory-synchronous A or B mode (trace #4) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous nested mode (trace#3) except that the stimulation bursts comprise A or B as in themanually-synchronized A or B mode (trace #1). The selected (A or B)stimulation burst will continue to be delivered on every respiratorycycle until the other burst is selected or until stopped. The linesbelow trace #4 indicate the time window during which a command willcause therapy to begin or change on the following inspiration.

The inspiratory-synchronous ABAB mode (trace #8) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous nested mode (trace#4) except that the stimulation bursts alternate between A or B on eachburst. The stimulation bursts will continue to be delivered on everyrespiratory cycle until stopped. The lines below trace #8 indicate thetime window during which a command will cause therapy to begin or end onthe following inspiration.

The inspiratory-synchronous toggle mode (trace #5) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous A or B mode (trace#4) except that the stimulation bursts are toggled. As shown, thetoggled stimulation burst sequence comprises 0A0B (i.e., no stimulation,stimulation level A, no stimulation, stimulation level B), whichcontinue to be delivered on each 4-breath series of respiratory cyclesuntil stopped.

The triggered toggle mode (trace #6) is similar in function to theinspiratory-synchronous toggle mode (trace #5) except that thestimulation burst sequence 0A0B is initiated and terminated by arecurring fiducial of the respiratory signal.

An example of a stimulation amplitude titration method is illustrated inFIG. 73A. In the illustration, three traces are shown: CPAP (pressure incm H₂O); STIM (stimulation amplitude in mA); and V_(imax) (maximuminspiratory nasal airflow in mL/min as measured by pneumotach or otherflow sensor). Initially, the stimulation amplitude is set to the capturethreshold, and the CPAP pressure is set to an efficacious level for agiven patient (typically above 5 cm H₂O and determined in a prior sleepstudy). In period “A”, the CPAP pressure is gradually decreased until aflow restricted state is reached in period “B” as detected by a drop inV_(imax). In period “C”, the stimulation amplitude is increased whilethe CPAP pressure remains constant until an unrestricted flow state isreached in period “D” as detected by a rise in V_(imax). In period “E”,the CPAP pressure is again gradually decreased until a flow restrictedstate is again reached in period “F” as detected by a drop in V_(imax).In period “G”, the stimulation amplitude is again increased while theCPAP pressure remains constant until an unrestricted flow state isreached in period “H” as detected by a rise in V_(imax). This iterativeprocess is repeated until the CPAP pressure reaches approximately 0 cmH₂O or until no further flow benefit is observed with increasingstimulation amplitude as shown in period “I”. The desired stimulationdose may be set to correspond to the lowest stimulation amplituderequired to mitigate restricted flow at a CPAP pressure of approximately0 cm H₂O or the lowest stimulation amplitude for which there is nofurther benefit in flow, whichever is lower. In addition, therapy can beadjusted to prevent flow restrictions at a nasal pressure slightly belowatmospheric to ensure efficacy under varying conditions that mayotherwise compromise airflow (e.g., head flexion, nasal congestion,etc.).

Another example of a stimulation amplitude titration method isillustrated in FIG. 73B. In addition to the stimulation amplitudetitration technique described above with reference to FIG. 73A,stimulation amplitude titration can be done through a different approachthat has two parts. The two parts are: with patient awake and withpatient asleep. These will henceforth be known as awake titration andsleep titration respectively. During awake titration, the stimulationamplitudes that cause the lowest level of muscle contraction, tonguedisplacement, and muscle contraction at the threshold of comfort arerecorded for the different frequency and pulse width settings.

This will be followed by a sleep titration, two examples of which areillustrated in FIGS. 73B and 73C. In FIGS. 73B and 73C, three traces areshown: CPAP (pressure in cm H2O); STIM (stimulation amplitude in mA);and CYCL (cyclic breathing associated with the patient's sleepdisordered breathing state). In addition, several points on the STIMtrace are indicated: ATHR (the arousal threshold, or the loweststimulation amplitude that causes arousal); CTHR (the capture threshold,or the lowest stimulation amplitude where muscle contraction iseffected). Traces not shown include those of respiratory flow and oxygensaturation level; although these variables are expected to be affectedby stimulation. An effect of stimulation on respiratory flow isdescribed with reference to FIG. 73A.

In FIG. 73B, sleep titration is carried out with the patient atatmospheric pressure and preferably in the supine position. However,this stimulation level titration is expected to be repeated throughoutthe sleep titration period with the patient in different conditions,including different body positions and sleep stages. After onset ofsleep, in region A, the patient is experiencing what to them would beconsidered severe sleep disordered breathing. Stimulation amplitude isalso periodically increased in region A. During these periodic increasesthe lowest stimulation amplitude that causes muscle contraction is alsoidentified. In region B, stimulation amplitude continues to beperiodically increased, which reduces the degree of but does not abolishthe sleep disordered breathing that the patient experiences. In region Cafter continued increase of the stimulation amplitude a level thatabolishes the sleep disordered breathing of the patient is achieved. Ifthis stimulation amplitude is reached in conditions considered to bemost challenging, then this stimulation level could be considered thetherapeutic level. In region D stimulation is turned OFF, which causesthe patient to go into sleep disordered breathing. In region E, thetherapeutic stimulation level is turned back ON and the patient's sleepdisordered breathing is abolished once again. In region F, continuedperiodic increase of stimulation amplitude leads to levels that causearousal. The arousal threshold is thus identified. In this titrationprocess, the stimulation level that abolishes the patient's sleepdisordered breathing without causing arousal and with the patient in themost challenging conditions is identified.

In FIG. 73C, sleep titration is started with the patient at atmosphericpressure. However, if a stimulation level that completely abolishessleep disordered breathing without causing arousal is not achieved, thensome sub-therapeutic CPAP (the patient's therapeutic CPAP will have beenidentified in a previous sleep study) could be used to complementstimulation for the delivery of therapy. After onset of sleep, in regionA, the patient is experiencing what to them would be considered severesleep disordered breathing. Stimulation amplitude is also periodicallyincreased in region A. During these periodic increases the loweststimulation amplitude that causes muscle contraction is also identified.In region B, stimulation amplitude continues to be periodicallyincreased, which reduces the degree of but does not abolish the sleepdisordered breathing that the patient experiences. In region C,continued periodic increase of stimulation amplitude leads to levelsthat cause arousal. The arousal threshold is thus identified. Note that,in this example, the stimulation level that causes arousal is reachedbefore the level that completely abolishes sleep disordered breathingcould be. In region D, a stimulation level that is just below thearousal threshold is maintained and the patient holds in moderate sleepdisordered breathing. In region E, a sub-therapeutic CPAP level thatabolishes the patient's disordered breathing is applied. This identifiesthe level of CPAP that complements stimulation in some patients. Inregion F, stimulation is either turned down or OFF from the level justbelow the arousal threshold, leading the patient to go into disorderedbreathing. In some cases, where the patients' sleep disordered breathingcannot be abolished by stimulation only, some CPAP pressure may be usedto complement stimulation. This could help increase the likelihood ofCPAP compliance of some patients since the CPAP pressure is reduced. Inaddition, it could help analyze how far patients are from beingcompletely treated by either stimulation or CPAP.

Another example of a stimulation amplitude titration method isillustrated in FIGS. 74A and 74B. This method may be carried out over aperiod of breaths (e.g., 4-10) or very slowly over several minutes(e.g., dozens of breaths to verify that optimal stimulation intensityhas been identified). In the illustration, four traces are shown: onetrace for CPAP pressure (designated by a solid diamond, pressure in cmH₂O); and three traces for V_(imax) (maximum inspiratory nasal airflowin mL/min as measured by pneumotach or other flow sensor) forstimulation amplitudes “0”, “A” and “B”. V_(imax) at stimulationamplitude “0” (designated by an open circle) corresponds to flow withstimulation off. V_(imax) at stimulation amplitude “A” (designated by anopen triangle) corresponds to flow with stimulation set to a value “A”,and V_(imax) at stimulation amplitude “B” (designated by an asterisk)corresponds to flow with stimulation set to a value “B”, where “A” isslightly less than “B”. Stimulation is delivered alternately at levels“A” and “B” with intermediate “0” levels (e.g., “0A0B”). Alternatively,stimulation may be delivered alternately at levels “A” and “B” withoutintermediate “0” levels (e.g., “AB”), which may be advantageous becausethe sequence may be executed faster and because arousal may otherwiseoccur due to low flow conditions at stimulation level “0”.

Initially, the CPAP pressure is set to an efficacious level for a givenpatient (typically above 5 cm H₂O and determined in a prior sleepstudy). With the stimulation amplitude set to “0” (i.e., stimulation isturned off), the CPAP pressure is gradually decreased while measuringV_(imax) to obtain a base-line reading when flow is un-restricted(beginning) and subsequently restricted. The stimulation amplitude isthen set to alternate between “A” and “B”, where “A” is set to thecapture threshold and “B” is set slightly higher than “B” (e.g., 0.1-1.0mA higher). The CPAP pressure is then gradually decreased (or droppedfor a short series of breaths and returned to baseline if needed tomaintain a passive state) while measuring V_(imax) to determine the flowat each stimulation level as shown in FIG. 74A. The values of “A” and“B” are incrementally increased and the CPAP pressure is again graduallydecreased while measuring flow. This iterative process is repeated untilthe traces converge as shown in FIG. 74B, demonstrating that no furtherbenefit in flow is realized with an increase in stimulation. The therapysetting may then be set to correspond to the lower stimulation amplitudevalue (“A”) where the traces for “A” and “B” converge. Note that FIGS.74A and 74B display the case where no arousal occurs during the gradualdecrease in CPAP pressure. In practice, it is expected that arousalswill occur before the process can be taken to complete conclusion asshown in the Figures. In the event of arousals, the iterative process isrepeated based upon convergence of the traces prior to the point ofarousal.

Another example of a stimulation amplitude titration method isillustrated in FIG. 75. FIG. 75 illustrates this method using astimulation sequence comprising “0A0B”, although a stimulation sequencecomprising “AB” may be used as an alternative. In FIGS. 75 and 18: “F”refers to peak inspiratory flow; “F.0” refers to flow with nostimulation; “F.A” refers to flow with stimulus intensity “A”; “F.B”refers to flow with stimulus intensity “B”; “OPEN” indicates that theairway is open, with no flow limitation; “Rx” indicates that the airwayis restricted (steady state flow limitation); “.uparw.S.A” (or“.uparw.S.B”) indicates that the intensity of stimulus “A” (or “B”)should be increased; “.dwnarw.P” indicates that CPAP (nasal) pressureshould be reduced; “.DELTA. S” is the difference between stimuli A andB; and “.DELTA.S=max” is when stimulus “B” is the maximum difference inintensity from stimulus “A” that will be tested (1.0 mA is recommendedfor this value).

Step 1 (holding pressure) in this method involves adjusting CPAP (nasal)pressure to the lowest holding pressure where maximum inspiratory flow(V_(i,max)) is not limited, and recording various data. Step 2 (attainoscillation/steady state flow limitation) involves reducing CPAP (nasal)pressure until flow oscillation occurs, recording data, increasing CPAP(nasal) pressure until oscillations cease, thereby achievingsteady-state flow limitation (SSFL), and recording data. Step 3(activation threshold, defined as lowest stimulation intensity with ameasurable effect on flow) involves selecting triggered toggledstimulation mode 0A0B with stimulation amplitude level A=stimulationamplitude level B=0.4 mA, and pulse width=30 microseconds (if no effect<90 microseconds, increment to 90 microseconds). Then, with stimulationamplitude level A=B, both amplitude levels A and B are incrementallyincreased until flow differs between stimulated breaths (level=A=B) andnon-stimulated breaths (level=0). If necessary, CPAP (nasal) pressuremay be adjusted to ensure SSFL during non-stimulated breaths. Step 4(optimize stimulation level) involves selecting triggered toggledstimulation mode 0A0B with stimulation amplitude level A=activationthreshold (determined in step 3) and stimulation amplitude levelB=smallest increment greater than level A, and then executing thefollowing sub-routine:

(a) While there is a significant difference in Vi,max (>10%) betweenStim A and B, increase both A and B amplitudes by same amount (0.1mA-0.5 mA) until no significant difference in Vi,max is observed;

(b) If Stim A breaths not flow limited, reduce CPAP (nasal) pressureuntil flow limitation is achieved and return to step (a); else, continueto (c);

(c) If Max Delta Stim (difference between Stim A and Stim B=1.0 mA, forexample) is reached, decrement CPAP (nasal) pressure; else increase StimB; continue to (d);

(d) Stop if either the lowest CPAP pressure level to be tested isreached (e.g., atmospheric or sub-atmospheric), or if maximumstimulation intensity of the INS is reached; else return to (a).

The therapy setting may then be set to correspond to the lowerstimulation amplitude value (“A” or “B”) where there is no increase inflow benefit. Optionally an additional margin may be added to thesetting (a fixed value or a percentage of the setting, e.g., 10% to 20%)to accommodate changing physiologic conditions.

FIG. 76A is a flow chart illustrating the method described withreference to FIG. 75. FIG. 76B provides a legend for the flow chart ofFIG. 76A.

From the foregoing, it will be apparent to those skilled in the art thatthe present invention provides, in exemplary non-limiting embodiments,devices and methods for nerve stimulation for OSA therapy. Further,those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

Treatment Overview

FIG. 82A illustrates a treatment overview from implant 10100, to awaketitration 10200, to daytime familiarization 10400, to sleep titration10500, to nighttime familiarization 10700, to up-titration 10800, andfinally to regular therapeutic use 11000 and therapy assessments 11100.

Beginning with a surgical implant 10100, FIG. 81 schematicallyillustrates the incision sites (solid thick lines) and tunneling paths(dotted lines) for implanting the INS 1100, STL 1300 and RSLs 1200. Theimplant procedure may be performed by a surgeon (e.g., otolaryngologist)in a 1-3 hour surgical procedure with the patient under general or localanesthesia, for example. In general, the implant procedure involvesplacing the cuff 1350 of the STL 1300 on the hypoglossal nerve via asubmandibular dissection, and tunneling the lead body 1330 and sigmoidsection 1370 of the STL 1300 subcutaneously down the neck to the INS1100 in a subcutaneous pocket in the infraclavicular region. From theinfraclavicular pocket, the RSL 1200 may be tunneled subcutaneouslytoward midline and then laterally along the costal margins.

After a healing period of a few weeks, an awake titration may beperformed 10200 wherein the patient's tongue response to stimulation isobserved over a range of comfortable stimulations, as illustrated inFIG. 82B. In addition, a global system check may be performed to checkthe system integrity. The patient is then sent home for a period ofdaytime familiarization 10400 where the patient may turn on stimulationduring wakefulness to introduce the sensation of stimulation. Thepatient subsequently returns to the sleep lab for a sleep titration10500 where a sleep technician, under the supervision of a certifiedsleep physician (e.g., pulmonologist), uses the programmer system 2100to program the INS 1100 (e.g., set the therapy delivery schedule andtitrate the stimulus to determine a range of efficacious settings duringsleep). After the sleep titration, the patient may return home and beginthe nighttime familiarization (acclimation) and therapy up-titrationprocess, wherein stimulation may be increased over time to anefficacious range. For example, the patient may leave the sleeptitration with stimulation programmed to turn on at 1.7 mA andstimulation may be increased by 0.1 mA at two week intervals up to agoal setting of 2.0 mA.

Immediately after the titration visit, the patient may return home andbegin using the device at the programmed stimulation level duringnighttime familiarization 10700. A therapy delivery session may beginwhen the therapy controller 2500 is used to manually start, stop, andpause a therapy session. This may be beneficial when the patient has anirregular sleep schedule. At the beginning of a therapy deliverysession, stimulus may be delayed for a period of time to allow thepatient to fall asleep. The therapy delivery session may be programmedto not exceed a fixed number of hours (e.g., eight hours). In addition,a therapy delivery session may begin according to the pre-definedtherapy delivery schedule, which may be set to coincide with when thepatient normally goes to sleep. The therapy delivery session may endaccording to the pre-defined therapy delivery schedule, which may be setto coincide with when the patient normally wakes up, or with a manuallystop command from the therapy controller. The patient may use thetherapy controller 2500 to adjust limited aspects of therapy delivery asdefined previously.

Tunneling System

FIGS. 69E and 69F schematically illustrate the tunneling system 3000which may be used for tunneling the STL 1300 or RSL 1200. The tunnelingsystem 3000 includes a relatively rigid tool 3010, a tubular sheath3020, and a tip 3030, and lead carrier 3100.

The tool 3010 may be formed of stainless steel and include a handle3016, a shaft 3012, and a distal connector 3018. The connector 3018includes threads that mate with corresponding threads in the tip 3030.The connector 3018 may also include ring barbs that form an interferencefit with the inside of the lead carrier 3100 for releasable connectionthereto.

The lead carrier 3100 may also form an interference fit with the RSLproximal connector 1210, the STL proximal connector 1310, or a distalring electrode of the RSL 1250 or 1260.

The sheath 3020 is sized to be slid over the tool 3010 and secured inplace via the tip 3030. The tip 3030 may include a radiopaque agent suchas barium sulfate loaded at 18% by weight, for example.

The lead carrier 3100 may comprise a small polymeric tube with an insidediameter sized to form an interference fit with the distal connector3018, the RSL proximal connector assembly 1210, an RSL distal electrode1250 or 1260, or the STL proximal connector assembly 1310. Duringtunneling, the proximal end of the lead carrier 3100 may attach to thedistal connector 3018 and the distal end of the lead carrier 3100 mayattach to the RSL proximal connector assembly 1210, an RSL distalelectrode 1250 or 1260, or the STL proximal connector assembly 1310.

The sheath 3020 may comprise a polymeric tube with two open ends, andthe tip 3030 may comprise a polymeric tube with one threaded end and oneclosed end for blunt dissection. The proximal end of the tip 3030includes internal threads to screw onto the connector 3018 and hold thesheath 3020 on the shaft 3012.

In the embodiment shown in FIGS. 69E and 69F, the tool 3010 may have apre-bend length of 17.1 inches and a post-bend length of 16.9 inches.The sheath 3020 may have an outside diameter of approximately 0.28inches, a pre-bend length of 12.4 inches and a post bend length of 12.25inches. The shaft 3012 may have a diameter of about 0.22 inches, apre-bend length of 12.375 inches, and a post-bend length of 12.231inches, sufficient to fill the length of the sheath 3020. The handle3016 may have a diameter of about 0.5 inches and a length of about 3.50inches. The tip 3030 may have an outside diameter tapering fromapproximately 0.13 inches and a length of about 1.0 inches.

Surgical Implant Procedure

With continued reference to FIG. 81, the internal components 1000 may beimplanted using the following surgical procedure 10100, which is givenby way of example, not limitation. Unless specifically stated, the orderof the steps may be altered as deemed appropriate. Although the INS 1100may be surgically implanted on the right or left side, the right side ispreferred to leave the left side available for implantation of cardiacdevices that are traditionally implanted on the left side. The rightside is also preferred for the RSL 1200 to provide a clean respiratorysignal that is less susceptible to cardiac artifact than the left side.

Standard surgical instruments may be used for incisions, dissections,and formation of subcutaneous pockets. Commercially available nervedissection instruments may be preferred for dissecting the hypoglossalnerve and placing the STL cuff 1350 on the nerve.

The patient is prepared for surgery using conventional practiceincluding standard pre-operative care procedures, administration ofantibiotics as appropriate, and administration of steroids asappropriate to reduce swelling around the nerve dissection. Becausetongue movement must be observed during test stimulation, it isrecommended that no long-acting muscle relaxants be used during surgicalpreparation or during implant. General anesthesia is administeredaccording to conventional practice and the patient is intubated using anendotracheal tube, taking care to position the endotracheal tube so thatthe tongue is free to protrude during test stimulation.

The neck is then extended to expose right submandibular region and asterile field is created around the neck and thorax, taking care toavoid obstructing visualization of the oral cavity (a clear steriledrape over the mouth may be used). By way of a neck incision (A), thehypoglossal nerve is then exposed deep to the submandibular gland.Because the INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing, this dissection isalso preferably performed on the right side. A region of the hypoglossalnerve, preferably excluding the branch that innervates retrusive muscles(e.g. styloglossus or hyoglossus), is then identified and isolated.Confirmation of correct nerve location may be achieved by performing atest stimulation later in the procedure. The identified nerve branch isthen circumferentially dissected to accommodate the cuff 1350. The shortside 1352 of the cuff 1350 is designed to reside on the deep side of thenerve, and the long side 1354 of the cuff 1350 is designed to reside onthe superficial side of the nerve.

The appropriate sized cuff 1350 is then selected based on the nervediameter at the intended location for cuff placement. Nerve size may beassessed using reference size (e.g., forceps of known width), a caliper,or a flexible gauge that wraps around the nerve, for example. The cuff1350 is then opened and placed around the nerve. The strap 1356 on thecuff 1350 may be used to facilitate placement of the cuff 1350 aroundthe nerve. A curved forceps may be placed under the nerve to grasp thestrap 1356 and gently pull the cuff 1350 onto the nerve. The strap 1356is then placed through the loop (buckle) 1358 on the cuff 1350. The cuff1350 may be available in two sizes (small and large), and the small cuffmay have an indicator mark (not shown) on the strap 1356 that should bevisible after insertion through the loop 1358. If a small cuff isselected and the indicator mark does not pass through the loop, thesmall cuff may be too small and should be replaced with a large cuff.

A strain relief loop (L) in the STL 1300 is then created by arrangingapproximately 6 cm of the STL sigmoid body 1370 in a C-shape inside asmall subcutaneous pocket formed via the neck incision (A) by bluntdissection superficially along the lateral surface of the digastricmuscle in a posterior direction.

The surgeon then verifies that the cuff 1350 is not pulling or twistingthe nerve, and that there is contact between the inside of the cuff 1350and the nerve.

A test-stimulation is then performed to confirm correct positioning ofthe cuff 1350 on the nerve. To conduct a test-stimulation, the proximalend of STL 1300 is plugged into the INS 1100 and the programmer system2100 is used to initiate a test stimulation signal delivered from theINS 1100 to the nerve via the STL 1300. The test stimulation isperformed while observing, for example, tongue movement by direct visualobservation, airway caliber by nasal endoscopy, fluoroscopy,cephalogram, etc. Correct placement of the cuff on the nerve may beconfirmed by, for example, observing tongue protrusion, an increase inretro-glossal airway caliber, an increase in retro-palatal airwaycaliber, an increase in stiffness of the anterior and/or lateral wallsof the retro-glossal airway with or without an increase in airwaycaliber, anterior movement without superior movement of the hyoid bone,among others. Incorrect placement of the cuff on the nerve is indicated,for example, when there is insufficient opening of the retro-palatal orretro-lingual space, when the tongue is observed to retract (posteriormovement), a decrease in retro-glossal airway caliber, a decrease inretro-palatal airway caliber, superior movement and particularlyunilateral superior movement of the hyoid bone, among others. Ifnecessary, the cuff 1350 may be repositioned at a different locationalong the length of the nerve to obtain the desired effect. The capturethreshold and impedance values are recorded and the STL 1300 isdisconnected from the INS 1100. The surgeon may create a fascia wrap bysuturing fascia around the cuff on the superficial side of the nerve.

A pocket for the INS 1100 is then created by making an incision (B) downto the pectoralis fascia approximately 2 finger breadths below the rightclavicle. The INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing. Blunt dissectioninferior to the incision is used to create a pocket large enough to holdthe INS 1100. The pocket should be inferior to the incision (B) suchthat the incision (B) does not reside over the INS 1100 when laterplaced in the pocket.

A tunnel is formed for the STL 1300 using the tunneling system 3000(sheath 3020 and tip 3030 placed over tool 3010) to tunnel along a path(C) from the infraclavicular INS pocket to the neck incision (A). Asshown in FIG. 69F, the lead carrier 3100 is then placed on the mostproximal electrical contact of the STL proximal connector 1310. The tip3030 is removed from the sheath 3020 to expose the connector 3018 of thetool 3010 and attach to the lead carrier 3100. While holding the sheath3020 in place, the tool 3010 is pulled proximally to pull back the STL1300 through the sheath 3020, taking care not to pull out the C-shapedstrain relief or disturb the cuff. If the C-shaped strain relief loop(L) is pulled out, it should be replaced into the small pocket. The tool3010 is released from the lead carrier 3100 and the lead carrier 3100 isremoved from the STL 1300. The sheath 3020 is then removed from the bodyleaving the STL 1300 in place. The neck incision (A) need not be closedat this time, but rather may be closed later in the procedure allowingconfirmation that the C-shaped strain relief remains in the smallpocket.

The following implant instructions refer to an INS 1100 implanted at thepatient's right sub-clavicular region. The right and left distalportions of the RSL 1200 are placed near the right and left costalmargins, respectively, by making four small incisions (D and E) asshown. The lateral incisions (E) may be made approximately 80% (+/−5%)of the distance from the midline to the mid-axillary line, and on thecostal margin. The medial incisions (D) may be made such that the RSL1200 is relaxed and all electrodes are on the costal margin. Using thetunneling system 3000 (sheath 3020, tip 3030 attached via connector3018), a tunnel (G) is formed between the pocket (B) and the medialincision (D), such that the right distal portion of the RSL 1200 may bepulled through the tunnel (G) from the pocket (B) to the medial incision(D). A tunnel (F) is then formed between the medial incision (D) andlateral incision (E), such that the right distal portion of the RSL maybe pulled through the tunnel (F) from (D) to (E). This is repeated forthe left distal portion of the RSL 1200. Alternatively, if theembodiments of RSL 1200 shown in FIG. 78F or 78G are used, a smallpocket may be formed medial to (D) in order to accommodate the medialelectrodes and/or loop back region 1255.

The previously described tunneling operations (F and G) may be performedas follows: The tunneling tool 3010 including the connector 3018 isinserted into the sheath 3020 and the tip 3030 is connected to theconnector 3018, forming the tunneling system 3000. The tunneling systemis placed in the origination incision site and pushed beneath the skintowards the destination incision site, forming a tunnel. Aftertunneling, the tip 3030 is removed from the connector 3018 of thetunneling tool 3010. If needed, the tool 3010 may be removed andreversed such that the connector 3018 is at the other end of the sheath3020. With the tool 3010 inserted through the sheath 3020, the leadcarrier 3100 is attached on its proximal end to the connector 3018 andon its distal end to the distal electrode 1250 or proximal connector1210 of the RSL 1200. While holding the sheath 3020 in place, thetunneling tool handle 3016 is pulled and the attached lead carrier 3100and RSL 1200 are pulled into the sheath 3020. This may be visualizedthrough the semi-transparent tunneling tool. The sheath 3020 may then beslid towards the tunneling tool handle 3016, exposing the lead carrier.The lead carrier may then be disconnected from the connector 3018,leaving the RSL 1200 in place. This process may be used to tunnel from(D) to (B) and subsequently from (E) to (D). For tunnel (G), the RSL1200 may be pulled completely through the sheath 3020 to expose anddisconnect the lead carrier.

Each anchor tab 1270 and suture hole 1290 is secured to the underlyingtissue by dissecting down to the adjacent muscle fascia and suturingeach anchor tab 1270 or suture hole 1290 to the muscle fascia. Permanentsutures are recommended to avoid movement of the RSL 1200 and braidedsuture material is recommended for knot retention and to preventcorrosion through the silicone anchors.

The STL 1300 and RSL 1200 are then connected to the INS 1100. The RSL1200 is plugged into the RSL port 1112 and the STL 1200 is plugged intothe STL port 1114. The set screws are tightened using a torque wrench.

A closed loop test may be performed to confirm proper operation byobservation of tongue protrusion or airway opening in concert withinspiration. The INS 1100 and proximal portions of the leads 1200/1300are then placed into the infraclavicular pocket, looping the excess leadlength beneath or around the INS 1100. Care should be taken not to pullout the C-shaped strain relief loop (L) in the STL sigmoid lead body1370 while manipulating the INS 1100 into place. The INS 1100 is thensutured to underlying fascia through both suture holes 1116 found in theheader 1110 of the INS 1100. Permanent sutures are recommended to avoidmovement of the INS both before tissue encapsulation and chronically,and braided suture material is recommended for knot retention. Anothersystem test may be performed at this point. After confirming that theC-shaped strain relief loop (L) is present in small pocket at neckincision, the incisions may be irrigated (optionally with an antibioticsolution) and closed using conventional techniques. After a healingperiod of approximately one month, the patient may undergo a sleep studyto confirm proper operation of the system and to titrate therapy.

Screening Methods

Prior to implant, patients may be screened to estimate the probabilityof a successful outcome.

The airway can be characterized during sleep by a Pcrit measurement indiffering sleep stages and body postures, per the methods of Schwartz etal. A higher Pcrit value is indicative of a more collapsible airwaywhich may be more difficult to treat with this therapy. A surrogatemeasure for Pcrit may be an auto-PAP device that adjusts airway pressuredynamically to eliminate flow limitation. For example, a patient mayrequire 12 cm H₂O of air pressure to maintain a patent airway in thesupine position, yet only require 8 cm H₂O of air pressure in thelateral position. The auto-PAP would automatically adjust for this.

The volume of air expired during a pressure drop may be measured. Thepressure drop may occur during natural expiration during wakefulness.Alternatively, the patient may be asleep during the measurement. Thetiming of the pressure drop during expiration may occur at a certainpoint during expiration to ensure consistency. The duration of thepressure drop may be fixed. An example of this measure is V_(NEP_0.5).

The airway may be visualized using an imaging modality such as, but notlimited to, cephalogram, MRI, fMRI, CT, ultrasound, OCT, naso-endoscopy,photography, and video imaging. This imaging may be performed duringsleep, under sedation, or during wakefulness. The patient may be askedto protrude the tongue, inhale/exhale at specific flow rates, or performMuller's Maneuver. Tongue protrusion force may also be measured. Tonguesize may be observed and/or measured quantitatively or qualitatively(e.g., Modified Mallampati). BMI may also be a good predictor of patientresponse.

The following metrics (and others) may be measured and used inscreening: size of tongue and soft palate, angle of the soft palate,redundancy of tissue, and length of soft palate. Endoscopy is one methodfor obtaining these metrics. Additional size metrics includecraniofacial structures, tonsil size, adenoids, pharyngeal fat pads.

Mechanical linkage or coupling between airway structures may also beassessed. For example, airway opening may be measured at differentlevels concurrent with other motions, (e.g. measuring opening of theairway at the retro-palatal space during voluntary tongue protrusion oranterior displacement of the tongue).

Nasal airway collapse may be measured using nasal peak inspiratory flowmeters in different body positions. Additionally, acoustic rhinometrymay provide another way to measure this.

Body Mass Index (BMI) may be a useful tool in screening. Additionalmetrics include % body fat, % visceral fat, neck circumference, % neckfat, and body fat distribution.

A patient's arousal threshold from sleep may be quantified by measuringintra-pleural arousal pressure. A nasal EPAP device may be used inscreening. An EPAP device reduces airflow through the nares. This mayincrease airway patency during the expiratory phase of respiration. Anexample of EPAP is the ProVent device (Ventus Medical Inc., BelmontCalif.). Arousals and respiratory events may be assessed with andwithout the EPAP device. During therapy, the patient's tongue mayprotrude past the teeth. A dental examination (i.e. identify sharpteeth), patient's use of dentures, and tolerance to oral appliances maybe used in screening.

The airway may be characterized using a dual air pump, and valve system,configured for connection to a mask on the patient. In thisconfiguration, the two different pressures (e.g., difference of 1 cmH₂O) are maintained by each pump which is connected to the valve. Thevalve may be attached via a tube to the mask such that the pressure atthe mask is from only one of the pumps. The valve may then be automatedto alternate between the two pressures at a programmable rate (e.g., 1Hz). This allows the airway to fluctuate between pressures withinbreaths. An airway may be characterized by lowering the pressure to alevel that brings flow limitation, and then observing what pressuresremove this flow limitation.

Awake Titration

As described previously, the patient may undergo an awake titration10200, an iterative process where the response to stimulation isdocumented over a range of comfortable stimulation levels (FIG. 82B).These stimulations may be delivered manually (e.g., 2 second commandedstimulation bursts) or synchronous with respiration. A range ofamplitudes may be tested across multiple frequencies (range of 20 to 50Hz, nominal 40 Hz), and pulse widths (range of 30 to 215.mu.s, nominal90.mu.s) 10220.

The awake titration may involve defining a wake-stimulation operatingwindow, defined at its lower limit by a capture threshold and at itsupper limit by a discomfort threshold. The capture threshold may bedefined as the lowest stimulation level at which muscle contraction isvisible, palpable, or perceptible (e.g., gross tongue movement orstiffening) is observed. The discomfort threshold may be defined as thelowest stimulation level at which the patient experiences anunacceptable sensation (e.g., discomfort, pain) while awake.

While determining this range, the patient may be in the supine positionor alternatively, in a posture typical of sleep. In general, during thestimulation titration, it is preferable to begin with the lowestsettings for pulse width (30.mu.s) and amplitude (0.4 mA) at a nominalfrequency (40 Hz). If stimulation produces pulsatile (vibrating)contractions, the frequency may be increased to 50 Hz. The pulse widthis incrementally increased to 60.mu.s, then to nominal (90.mu.s),keeping Amplitude at 0.4 mA. With the pulse width set to 90.mu.s,amplitude may be iterated according to the process describedhereinafter. If maximum amplitude is reached and additional intensity isrequired, the pulse width may be increased while reducing amplitude tominimum (0.4 mA). If maximum pulse width (215.mu.s) is reached andadditional intensity is required, frequency may be increased whilereducing the pulse width to 90.mu.s and the amplitude to minimum (0.4mA).

At each stimulation level, observations may be recorded such as: visibletongue motion, palpable genioglossus muscle contraction, perception ofmuscle movement, tongue protrusion, tongue retrusion, tongue depression,tongue flattening, tongue cupping, and tongue protrusion past the teeth10230.

After awake titration 10200, the patient may be sent home at astimulation level in this operating range, beginning the daytimefamiliarization period 10400. This may occur prior to the sleeptitration night, such that the patient may acclimate to the sensation ofstimulation. This may allow higher levels of stimulation to be assessedduring the sleep titration without patient arousal. Patients have beenobserved to tolerate (i.e., not arouse) higher stimulation intensitieswhile asleep compared to wakefulness, so the arousal threshold may behigher than the wake discomfort threshold.

Sleep Titration

As described previously, after implantation and a healing period ofapproximately one month, the patient may undergo a sleep (PSG) study toconfirm proper operation of the system and to titrate therapystimulation levels 10500. Titration may utilize the set-up illustratedin FIG. 10, wherein the programmer system 2100 interfaces with the PSGequipment 2800. Generally, it is preferable to use an oro-nasal mask inorder to measure airflow. Alternatively, a nasal cannula may be used.The preferred configuration is a calibrated pneumotach with theoro-nasal mask to measure the patient's airflow 10510. Alternatively, anuncalibrated pneumotach may be used. A thermistor or a thermocouple mayalso be used to sense airflow. The thermistor or thermocouple may becalibrated or uncalibrated.

FIG. 84 illustrates an example of a patient's airflow response tostimulation. As shown in FIG. 84, the inspired airflow increases asstimulation delivered to the nerve increases. The airflow capturethreshold is the stimulation level at which an increase in airflow isfirst observed. As stimulation continues to increase, muscle (i.e.genioglossus) activation and airflow also increase. Prior to full muscleactivation, a stimulation level which first removes respiratory eventsis observed. At full muscle activation, increasing stimulation does notincrease airflow, resulting in an airflow plateau. The patient mayarouse due to stimulation at a level on the plateau. Data comprisingthis curve may be acquired during a sleep titration PSG for eachpatient.

The sleep titration process is illustrated schematically in FIG. 82C.Titration generally involves establishing an effective range ofstimulation settings 10540, where the lower end is defined by the loweststimulation level where respiratory events (e.g., apneas, hypopneas,oxygen desaturations, etc.) 10550 begin to decrease or airflow begins toincrease, and the range's upper end is defined by stimulation thatarouses the patient. A goal setting at which the patient is effectivelytreated (i.e. respiratory events removed) may be estimated.

During a sleep titration, device settings may be programmed using theprogrammer system 2100. At the start of titration, most stimulationsettings will be at their default values (40 Hz frequency, 90 uS pulsewidth, 50% stimulation duty cycle, 0 ms phase adjust, etc.). Titrationtypically consists of many series of “ramps” in different body positionsand sleep stages, wherein each ramp is a series of intervals where thestimulation intensity is increased from the previous interval in acertain stimulation mode 10540, illustrated in FIG. 83. For example, at40 Hz, 90 uS, in A0A0 mode, stimulation level of the “A” breaths couldbe incremented every two minutes, from the nerve capture amplitude tothe amplitude that causes arousal, as illustrated in FIG. 83 trace 3.Ramps are typically performed in A0A0, ABAB, AABB, A0B0, or AAAA modes,as illustrated in FIG. 83, traces 1, 2, 3, and 5. In addition, ramps maybe performed using any of the previously discussed modes, also shown inFIG. 83. At each interval, observations are made as to whetherstimulation causes arousal, reduces respiratory events, or increasesairflow (e.g., increased V_(i,max)).

Alternative stimulation modes (not illustrated) may be utilized duringwakefulness or sleep, (e.g. during a sleep titration PSG). Analternative mode may be xAy0 mode, where stimulation is delivered for“x” breaths wherein “x” is a programmable number of breaths, followed by“y” breaths with no stimulation wherein “y” is a programmable number ofbreaths. For example, in mode 4A40, stimulation is delivered on fourconsecutive breaths followed by no stimulation on four consecutivebreaths.

A0A0 mode may be useful in determining if a stimulated breath has moreflow than an adjacent unstimulated breath. In the same manner, ABAB andAABB modes may be useful in determining if a stimulated “A” breathprovides more flow compared to an adjacent breath with less stimulation,“B.” Likewise, A0B0 mode may be useful in comparing flows during “A”stimulation, “B” stimulations, and unstimulated breaths. During a ABAB,AABB, and A0B0 ramps, the difference in stimulation between “A” and “B”stimulations may be constant. ABAB, AABB, and AAAA ramps may also beuseful in determining absolute flow (e.g., tidal volume, minute volume,etc.) and determining what level of stimulation reduces or eliminatesrespiratory events, since stimulation is delivered every breath. Theseobservations may be recorded for future reference (e.g. physician use).Each stimulation mode may be combined with any of the pulseconfigurations, such as nested stimulation, soft start, or retentionintensity, as chosen by physician or technician.

When a stimulation level is estimated to be efficacious, it may betested in AAAA mode for a fixed time (e.g., five minutes) after whichstimulation may be turned off for a fixed time (e.g., five minutes). Ifstimulation noticeably reduced or eliminated respiratory events comparedto no stimulation, the settings may be considered the goal setting.

Additional titration PSG studies may be performed, either as a separatesleep study or as a split night study. In order to compare multiplestimulation settings during sleep, a cross-over PSG study may beperformed wherein the stimulation settings are changed at fixedintervals throughout the night, toggling through a select group ofsettings. For example, stimulation may alternate between two stimulationsettings every five minutes. Afterwards, respiratory events may bedetermined for each interval such that an index (e.g., AHI, ODI, etc.)can be calculated for each stimulation setting. This may be useful togauge whether an increase in stimulation would provide additiontherapeutic benefits or to gauge whether a decrease in stimulation wouldnot lessen any therapeutic benefits. In addition, the oxygen sensor ofthe INS 1100 may be used to measure oxygen de-saturations and calculatean ODI.

Another type of titration PSG may be a characterization night, per themethods of Schwartz et al, such that a Pcrit may be determined inREM/nREM sleep, both supine and lateral. Another type of sleep study isthe home PSG study, which may be utilized to assess efficacy without theburden of an in-lab PSG. Many home PSG systems are available for use.

The patient may also undergo a vector-sweeping sleep study, wherein theprogramming system 2100 and a respiratory signal (e.g., nasal cannula)are utilized, 10520. During this study, the secondary vector may bechanged at regular intervals to cycle through a select group of vectors.These vectors are compared to the primary vector to determine an optimalsensing vector to deliver therapy. Selection may be based on maximumsignal strength, consistent correlation to respiratory fiducials (e.g.,offset of inspiration), and maximum signal stability/reliability acrosssleep stages, body positions, and disordered breathing events, forexample. A stable signal has a minimum probability of signal inversion.A reliable signal has a minimum probability of signal loss, and maypreferably have a minimum threshold of 0.1 to 0.5 Ohms peak-to-peak, forexample. The optimal vector may be selected by incrementally scrollingthrough all or a preferred subset of possible vectors while sampling therespiration signal and comparing the signal against themselves orpredefined thresholds. This scrolling technique may be performedmanually (with inputs via the programmer system) or automatically (i.e.,programmed). The sampling technique may also be performed manually(visual observation using programmer system) or automatically (i.e.,programmed).

Post-Sleep-Titration: Nighttime Familiarization and Up-Titration

After titration, the patient is typically sent home with the deviceactive and stimulation set to a level at which she can fall asleep. Thisbegins the post-sleep-titration process, as illustrated in FIG. 82D.This process may include nighttime familiarization, up-titration ofstimulation, and determining efficacy 10700, 10800, and 11100.

The stimulation settings at which the patient is sent home may initiallybe below the estimated goal settings. As the patient becomes acclimatedto sleeping with the device on 10700, stimulation may be slowlyincremented, over the course of days, towards the range wheretherapeutic effects were observed during the sleep titration andultimately towards the estimated goal settings. This period is known asup-titration 10800. These increments may be performed by a physician orcaretaker, or by the patient, if the physician allows the patient tohave limited control of stimulation via the therapy controller 2500.

Several feedback parameters may aid in determining the appropriate timeto up-titrate a patient 10810. These include the device's therapyhistory of frequency and duration of therapy sessions, patient feedback(e.g., more daytime energy, no tongue abrasions, stimulation not causingarousal or pain, etc.), patient's bed-partner feedback (e.g., reducedsnoring, perceives patient to be less sleepy, etc.), and most notably, aPSG study. Taken together, these may show whether the patient needs moretime to acclimate to stimulation, is ready to have stimulation increased10840, is receiving therapeutic benefits, or is fully treated. Inaddition, these feedback may provide data to adjust the patient'sestimated goal settings 10820. For example, a patient's upper airwaymay, over time, undergo muscle remodeling such that less stimulationthan originally estimated provides efficacious therapy. Alternatively, apatient may gain weight such that more stimulation than originallyestimated may be needed to provide efficacious therapy.

If the stimulation is causing discomfort to the patient such thatstimulation disrupts sleep or inhibits falling asleep with stimulationon, many options are available, 10830. Stimulation may be reduced andthe patient may be given more time for nighttime familiarization. Adifferent strategy that may increase the therapy provided to the patientis to utilize the device features of core hours, soft start, retentionintensity, and nested stimulation. The core hours feature (FIG. 6K)allows the patient to fall asleep at one level of stimulation and aftera programmable time interval, have stimulation increased to a moretherapeutic level. Patients are often able to tolerate higherstimulations when asleep compared to wakefulness and in addition,tolerate higher stimulations further into a therapy session than at thestart of a session.

As mentioned previously, the INS 1100 may be programmed to changestimulation level between therapy sessions, days, or other programmablevalue, enabling comparisons between stimulation level and therapysession data. For example, the INS 1100 may be programmed to alternatebetween 1.8 mA and 2.0 mA, where the change occurs between therapysessions. This may be used as a diagnostic mode to assess theincremental benefit of the higher stimulation level. A patient receivingdaily therapy would thus receive therapy at 1.8 mA on one day, 2.0 mAthe next, 1.8 mA the next day, 2.0 mA the next day, and so on. This mayallow therapy session data to be compared with stimulation level. Forexample, a physician may compare the cycling rate (via the cyclingdetector) during therapy sessions at 1.8 mA and 2.0 mA over time todetermine if there is an observable difference. If cycling is reduced at2.0 mA, the physician may increase stimulation and re-test. If there wasno observable difference, the physician may decrease stimulation andre-test or simply set stimulation to the lower level. This may reducethe likelihood of delivering stimulation at a level that, compared to alower level, provides no additional flow or no additional benefit. Asmentioned previously, other therapy session data may be compared tostimulation level as well in a similar manner. Examples of other therapysession data are: oxygen desaturation frequency and severity,stimulation time, variations in respiratory rate, and variations inrespiratory prediction.

Various pulse configurations may also help a patient acclimate tostimulation. The soft start stimulations (FIG. 80G) may provide asmoother transition from unstimulated breaths to stimulated breaths,reducing the patient's perception of stimulation intensity. Retentionintensity (FIGS. 80E and 80F) may also provide therapy with reducedpatient perception of stimulation intensity, since the full amplitude isonly used for a part of the stimulation. Nested stimulations (FIG. 80H)may be used in a similar manner.

The patient may use positive airway pressure (PAP) therapy (e.g., CPAP,bi-PAP, auto-PAP, etc.) in conjunction with the neurostimulator. Thismay allow the patient to receive therapeutic benefits in addition towhat is provided by the stimulation. The pressure necessary to providethese benefits may decrease as stimulation is up-titrated, 10800. Thisprogress towards lower pressures may be monitored using the auto-PAPtechnology which automatically adjusts pressure to the level necessaryto remove flow limitation. In time, the patient may wish to stop PAPtherapy altogether. In a similar manner, other therapies such as but notlimited to positional therapy and mandibular advancement may be used inconjunction with the neurostimulator.

If the patient begins noticing tongue abrasions, a tooth guard or othertooth covering (e.g. dental wax) may be used such that the tongue doesnot scrape against the teeth when stimulation causes tongue protrusion.Tooth guards may be custom-made (e.g., by a dentist).

Additional strategies for acclimation may include another sleeptitration night to examine different stimulation frequencies, pulsewidths, and modes, as previously described. Different stimulationfrequencies and pulse widths may capture different muscle groups in amore therapeutic manner. In additions, respiration vectors may need tobe assessed during a vector sweeping titration.

Therapy efficacy may be measured using standard PSG techniques duringand after familiarization and up-titration. Therapy efficacy may beevaluated by assessing indicia of sleep disordered breathing such asAHI, apnea index, hypopnea index, respiratory disturbance index,apnea-hypopnea index, ODI, FOSQ, ESS, BDI, PSQI, or other measures.

Alternative Embodiments

The stimulation may be delivered to the nerve by utilizing a variety ofstimulation electrode configurations, in addition to the configurationspreviously mentioned.

Mono-polar stimulation may be delivered to the nerve wherein the cathode(or multiple cathodes) is an electrode (or multiple electrodes) in theSTL nerve cuff 1350, and wherein the anode is the INS 1100. Similarly,far-field bi-polar stimulation may be delivered to the nerve wherein thecathode (or multiple cathodes) is an electrode (or multiple electrodes)in the nerve cuff, and wherein the anode is an RSL electrode 1250 or1260.

Any combination of bi-polar and mono-polar stimulation may be utilizedto deliver stimulation to the nerve. For example, mono-polar stimulationmay be delivered between a cathode electrode in the STL nerve cuff 1350and the INS 1100 anode. Simultaneously, far-field bi-polar stimulationmay be delivered between a different cathode electrode in the STL nervecuff 1350 and an RSL electrode 1250 or 1260 anode.

The INS 1100 may be programmed to periodically change stimulationparameters throughout a therapy session to vary which muscle fibers arerecruited at any given time. For example, stimulation may be deliveredat an initial lower frequency (e.g. 30 Hz) for 5 minutes, followed bystimulation delivered at a higher frequency (e.g. 50 Hz) for 2 minutes.Each frequency may have a unique pulse width, pulse width, and/oramplitude. This sequence could be repeated throughout the night.

This may allow certain muscle fibers to rest during periods when othermuscle fibers are active. This may reduce muscle fatigue. Anotherpotential advantage is that stimulation at more than a single frequencyand/or pulse width may be a more effective means of building musclestrength and endurance. Another potential advantage is that differentstimulation settings (e.g. frequency, pulse width, and/or amplitude) mayresult in slightly different movement of the tongue. Varying stimulationsettings may decrease the possibility of repetition-induced irritation,inflammation or injury.

Alternatively, it may be possible to effectively build muscle strengthand endurance by deactivating a portion of the nerve fibers andactivating a remaining subset of fibers. This may allow delivery ofhigher levels of stimulation to the remaining fibers. This may reducesubject discomfort which could have occurred if all the fibers had beenactivated at that same intensity. Additionally, this may increase airwaypatency or opening by selecting muscles whose activation results intongue protrusion and deactivating tongue retrusion muscles.

Certain fibers in the nerve may be selectively deactivated by choosingthe cathode of pulse delivery and sequence of pulse delivery such thatthe fibers are not recruited by subsequent or simultaneous pulses. Forexample, a nerve fiber that innervates a retrusor muscle may bedeactivated by delivering a sub-threshold pulse from a nearby cathode.This may allow a subsequent or simultaneous pulse at a different cathodeto activate a nerve protrusor muscle nerve fiber without recruiting theretrusor muscle.

Screening Devices and Methods

FIG. 86 schematically illustrates an exemplary hypoglossal nervestimulation (HGNS) system 100 comprising internal components 1000 andexternal components 20000. The HGNS system 100 is intended to treatobstructive sleep apnea (OSA) by increasing neuromuscular activity ofthe genioglossus muscle via stimulation of the hypoglossal nerve (HGN)synchronous with inspiration to mitigate upper airway collapse duringsleep. Stimulation is generated by an implantable neurostimulator (INS)1100, synchronized with inspiration as measured by the respirationsensing lead (RSL) 1200 using bio-impedance, and delivered to thehypoglossal nerve by a stimulation lead (STL) 1300. Alternatively,stimulation may be delivered without respect to respiration, negatingthe need for respiration sensing capability. A programmer system 2100and a therapy controller 2500 are wirelessly linked to the INS 1100. Theprogrammer system 2100 includes a computer 2300, a programmer interface2400, and a programmer head 22000. The programmer system 2100 is used bythe physician to control and program the INS 1100 during surgery andtherapy titration, and the therapy controller 2500 is used by thepatient to control limited aspects of therapy delivery (e.g., start,stop, and pause).

The implanted components 1000 of the HGNS system 100 include the INS1100, STL 1300, and RSL 1200. The INS is designed to accommodate one STL1300 and one RSL 1200. One STL 1300 may be used for unilateralimplantation and unilateral hypoglossal nerve stimulation. Similarly,one RSL 1200 may be used for respiration detection, and may bebifurcated as shown.

The implanted components 1000 may be surgically implanted with thepatient under general anesthesia. The INS 1100 may be implanted in asubcutaneous pocket inferior to the clavicle over the pectoralis fascia.The distal end of the STL 1300 (cuff 235) may be implanted on thehypoglossal nerve or a branch of the hypoglossal nerve in thesubmandibular region, and the proximal end of the STL 1300 may betunneled under the skin to the INS 1100. The RSL 1200 may be tunneledunder the skin from the INS 1100 to the rib cage and placed on bothlateral sides of the costal margin. The INS 1100 detects respiration viathe RSL 1200 using bio-impedance and stimulates the hypoglossal nervevia the STL 1300 synchronous with inspiration.

Further aspects of the HGNS system 100 may be found in U.S. ProvisionalPatent Application No. 61/437,573, filed Jan. 28, 2011, entitledOBSTRUCTIVE SLEEP APNEA TREATMENT DEVICES, SYSTEMS AND METHODS, theentire disclosure of which is incorporated herein by reference.

Patients with obstructive sleep apnea have repeated episodes of complete(apnea) or partial (hypopnea) upper airway collapse during sleep. Theupper airway is generally defined by four walls: the posteriorpharyngeal wall, the right and left lateral pharyngeal walls, andanteriorly, the soft palate and the tongue. The posterior pharyngealwall is relatively fixed to the spinal column. Thus, collapse of theupper airway generally involves, depending on the level and mode ofcollapse, the tongue, the soft palate and/or the lateral walls. In rarecases, collapse may involve the nasopharynx and/or hypopharynx. As seenin FIG. 87A, the tongue and the soft palate have been displacedposteriorly, thus occluding the airway at the level of the tongue(retro-glossal collapse) and at the level of the soft palate(retro-palatal collapse). As seen in FIG. 87B, activation of thegenioglossus muscle, for example by HGNS, causes anterior displacementof the tongue, thus opening the retro-glossal airway space. Activationof the genioglossus muscle can also cause anterior displacement of thesoft palate, thus opening the retro-palatal airway space. Although notvisible in this view, activation of the genioglossus muscle can furthercause lateral displacement of the lateral pharyngeal walls, thus furtheropening the upper airway. In this manner, activation of the genioglossusmuscle, for example by HGNS, can mitigate upper airway collapse in OSAsubjects.

Although the effect of genioglossus activation on the tongue to open theretro-glossal airway is predictable given the mechanism of action, theeffect of genioglossus activation on the soft palate and lateral wallshas been heretofore poorly understood and variable across subjects.Nevertheless, in the majority of OSA patients, the soft palate and thelateral walls can contribute to upper airway collapse, alone or incombination with the tongue. Thus, observing these effects can beimportant to predicting the success of HGNS therapy. This isparticularly true if the soft palate and/or lateral walls are known tocontribute to airway collapse for a given OSA patient.

The present invention offers a method to mimic genioglossus activationto observe and assess the effects thereof on structures of the upperairway. The method generally involves causing the tongue to protrudewhile observing the response of the upper airway using an imagingtechnique. In general, the desired response is an increase in airwaysize. An adequate increase in airway size during the tongue protrusionmaneuver is indicative of likely therapeutic success with HGNS. If anadequate increase in airway size is observed during the maneuver, a HGNSdevice may be implanted in the patient with a higher confidence of asuccessful outcome.

With reference to FIG. 88A, a naso-endoscope 4000 may be used tovisually observe the upper airway while the patient is awake in thesupine position. Alternatively, the observation may be made while thepatient is in a seated or semi-recumbent position. A conventionalnaso-endoscope 4000 including a fiber optic shaft 4100 and a hand piece4200 may be used. Hand piece 4200 may include a light source and aviewing window, and/or facilitate connection to ancillary imagingequipment (e.g., light source, camera, monitor, recorder, etc.). Thepatient may be asked to volitionally protrude his/her tongue straightand to its maximal extent with the mouth open and the lips looselytouching the tongue. Alternatively, the tongue protrusion may beperformed sub-maximally, which may limit muscle contraction to thegenioglossus without recruiting other musculature. Also alternatively,the tongue protrusion may be performed by asking the patient to pointthe tip of the tongue to one side or the other, which may more closelymimic unilateral hypoglossal nerve stimulation. The distal end of theendoscope may be positioned superior to the soft palate andsubstantially parallel with the posterior pharyngeal wall to visualizethe retro-palatal space. The distal end of the endoscope may bepositioned inferior to the soft palate, superior to the tongue base andsubstantially parallel with the posterior pharyngeal wall to visualizethe retro-glossal space. An example of the view of the retro-palatalupper airway space with the tongue in a relaxed (nominal) position isshown in FIG. 88B, and the same view with the tongue protruded is shownin FIG. 88C. As can be seen by comparing the views in FIGS. 88B and 88C,tongue protrusion can result in an increase in airway size, includingarea, circumference, anterior-posterior dimension, and lateraldimension. The increase in airway size at the level of the tongue andpalate may be most discernable by an increase in anterior-posterior (AP)dimension between the posterior pharyngeal wall and the posterior sideof the tongue base (retro-glossal) and soft palate (retro-palatal),respectively. Since the posterior pharyngeal wall is fixed relative tothe spinal column, the increase in AP dimension involves anteriordisplacement of the tongue and soft palate, respectively. The increasein airway size may also be discernable by an increase in lateraldimension between the right and left lateral pharyngeal walls.

During the tongue protrusion maneuver, observing an adequate increase insize of the retro-glossal airway is predictive of HGNS efficacy inpatients with isolated tongue base collapse. However, as mentionedabove, the soft palate contributes to upper airway collapse in themajority of OSA patients, thus also observing an increase in size of theretro-palatal airway during the tongue protrusion maneuver is predictiveof HGNS efficacy in patients with isolated soft palate collapse andcombined tongue plus soft palate collapse.

By way of example, not limitation, the following procedure may befollowed to conduct the assessment and tongue protrusion maneuver. Withthe patient awake in the supine position, a nasal endoscope is insertedinto the pharynx via one of the nares to allow visualization of theupper airway. Video and still images may be captured at both theretro-palatal and retro-glossal levels to document the effect ofdifferent maneuvers on anatomic structures of the upper airway (tongue,palate, epiglottis, pharyngeal walls, etc.). When imaging theretro-palatal level, the endoscope may be placed such that all fourwalls (soft palate, posterior wall, and the two lateral walls) of thepharynx are visible before, during and after maneuvers. Similarly, whenimaging the retro-glossal level, the endoscope may be placed such thatall four walls (tongue base, posterior wall, and the two lateral walls)of the pharynx are visible before, during and after maneuvers. Theendoscope may be placed such that it runs generally parallel to theposterior wall and provides a symmetric field of view. This may beachieved by initially placing the distal end of the endoscope near thelevel of the epiglottis and subsequently pulling back to the desiredlevel. The patient then performs a series of maneuvers, including atongue protrusion maneuver while breathing through their nose. Thetongue protrusion maneuvers involves voluntary maximal straight tongueprotrusion with lips loosely touching the tongue, with the mouthcompletely open, and/or with the teeth clenched closed. Other maneuverssuch as a Mueller maneuver (inspiratory efforts against a closed airway)may be performed as well. Each maneuver is held for .gtoreq.2 seconds,and performed several times while data (images and measurements) aregathered.

Alternative non-volitional tongue protrusion maneuvers include, forexample, manually gripping and pulling the tongue anteriorly (e.g., bythe physician), using a tongue retaining device (e.g., as used for thetreatment of OSA), both of which are non-invasive. Another alternativeis to stretch the palatoglossal arch by pushing the tongue down (depresstongue), by pushing the arch laterally outward, or by pulling the archanteriorly (all palatoglossal maneuvers) using a tongue depressor orsimilar device. The palatoglossal maneuver may be used in place of or incombination with the tongue protrusion maneuver, and the entiredescription herein with respect to the tongue protrusion maneuver isapplicable to the palatoglossal maneuver. Other alternativenon-volitional tongue protrusion maneuvers include, for example,sub-mental stimulation and intra-muscular stimulation (using fine wireelectrodes, for example), both of which are relatively more invasive,but have the benefit of more selectively activating the genioglossusmuscle alone to more closely mimic HGNS, as compared to volitionaltongue protrusion which may recruit more than the genioglossus muscle.

Although naso-endoscopy is perhaps the most practical imaging techniqueto employ to assess the response of the upper airway to the tongueprotrusion maneuver, other imaging techniques may be used as well. Forexample, x-ray imaging, fluoroscopy, x-ray computed tomography (CT), andoptical coherence tomography (OCT) are suitable alternatives. Thesealternatives may provide more quantitative measurements by using areference marker of known dimension in the field of view. Alternatively,improvements may be made to conventional naso-endoscopes to facilitatemore quantitative measurements. For example, with reference to FIG. 88D,conventional naso-endoscope 4000 includes a fiber optic shaft 4100 and ahand piece 4200. The distal end of the shaft 4100 may include anattached extension 4300 having a tip 4400. The extension 4300 positionsthe tip 4400 into the field of view and may be approximated to the upperairway structure being visualized. The tip 4400 may have a knowndimension (e.g., diameter of 1 French or 3 mm), such that quantitativemeasurements of upper airway structures may be made by comparison. Otherdevices to make quantitative measurements may be employed, such as alaser pointer of know beam diameter projected onto the upper airwaystructure of interest. As an alternative, a catheter (e.g., nasogastric,nasoesophageal or nasopharyngeal catheter) may be inserted into thenasopharynx such that it resides in the field of view of the endoscopeto serve as a quantitative reference of known dimension (e.g.,diameter).

As mentioned above, the upper airway assessment during tongue protrusionmaneuver may be used as a screening tool wherein the patient is treatedwith the desired therapy (e.g., HGNS) only if the increase in size ofthe upper airway meets a predefined criterion. To this end, the responseof the upper airway may be measured using a qualitative scale such as avisual analog scale of 0-10, wherein 0 represents a closed airway and 10represents a completely open or patent airway. The airway size may bescored with the tongue at rest and during the tongue protrusionmaneuver. The patient may be treated if the difference between the twoscores meets a threshold, if the score during the maneuver meets athreshold, or if both the difference between the scores and the scoreduring the maneuver meet thresholds (e.g., 5 on a scale of 0-10).

Alternatively, the response of the upper airway may be measured using aquantitative scale such as: a pixel count of captured images which maybe representative of cross-sectional area; a linear dimension such asanterior-posterior and/or lateral; or a measure of circumference. Hereagain, the airway size may be measured (e.g., pixel count, AP length,and/or lateral width) with the tongue at rest and during the tongueprotrusion maneuver. The patient may be treated if the differencebetween the two measures meets a threshold, if the measure during themaneuver meets a threshold, or if both the difference in measures andthe measure during the maneuver meet thresholds.

In each case, the threshold may be a percentage increase in size (e.g.,difference in AP length=50%), an absolute value (e.g., difference of APlength=0.5 cm), or a relative value. The relative value may be withreference to an anatomical landmark such as the width of the superioraspect of the epiglottis (e.g., difference in AP length=50% ofepiglottal width).

Other response criteria observed during the tongue protrusion maneuver,in addition to an increase in airway size, may be used as well. Forexample, movement of the hyoid bone may be observed visually, bypalpation or by x-ray. Movement of the hyoid bone in an anteriordirection and/or inferior direction during the tongue protrusionmaneuver may be predictive of therapeutic success with HGNS.

As mentioned above, although the effect of HGNS and genioglossusactivation on the tongue to open the retro-glossal airway is predictablegiven the mechanism of action, the effect of genioglossus activation onthe soft palate and lateral walls has been heretofore poorly understood.The explanation lies in the mechanical linkages between the genioglossusand other pharyngeal structures defining the upper airway. The linkagesare primarily muscular, and can be effective without independentactivation. Nevertheless, it may be desirable to independently activateany one or a combination of the muscular structures described below bystimulating the muscle directly or by stimulating the correspondingmotor nerve innervating the muscle.

With reference to FIG. 89, the mechanical linkages may be explained inmore detail. By way of context, the hypoglossal nerve (cranial nerveXII) innervates the genioglossus muscle, which is the largest upperairway dilator muscle. Activation of the genioglossus muscle causestongue protrusion and, in some cases, anterior displacement of the softpalate, due to linkage via the palatoglossal arch (muscle). Anteriordisplacement of the soft palate, in turn, can cause tension to beapplied to the lateral pharyngeal walls via the palatopharyngeal arch(muscle), the effect of which is discussed in more detail below. Thus,activation of the genioglossus muscle causes opening of the upper airwayat the level of the tongue base (retro-glossal space) and, in somecases, at the level of the soft palate (retro-palatal space). Becausethe linkage between the genioglossus and the soft palate via thepalatoglossal arch varies across subjects, the response to HGNS at thelevel of the palate will vary as well. This is significant because mostpeople with OSA have some involvement of the palate during obstructiveevents, and it may be helpful to identify those subjects with inadequateretro-palatal opening due to poor linkage (i.e., poor coupling) betweenthe genioglossus and soft palate, possibly due to tissue redundancy(i.e., slack) in the palatoglossus. Tissue redundancy may also bepresent in the lateral pharyngeal walls due to the presence of adiposetissue (i.e., fat) at discrete locations (e.g., fat pads) or distributedthroughout the pharyngeal walls, particularly in patients with high BMI.

The anatomical linkage between the tongue base (genioglossus) and thesoft palate via the palatoglossal arch may be more clearly seen in FIGS.90 and 91. The palatoglossus muscle forms the palatoglossal arch and theanterior-inferior aspect of the soft palate on either side of the uvula.The inferior and lateral ends of the palatoglossus muscle insert intothe genioglossus muscle. Posterior to the palatoglossal arch are thepalatine tonsils, and posterior to the palatine tonsils is thepalatopharyngeus muscle forming the palatopharyngeal arch and theposterior-inferior aspect of the soft palate on either side of theuvula. The inferior and lateral ends of the palatopharyngeus muscleinsert into the lateral walls of the pharynx. The soft palate is alsolinked to the lateral pharyngeal walls inferiorly via thepharyngoepiglottic fold as best seen in FIG. 92. Activation of thegenioglossus serves to pull the soft palate anteriorly via thepalatoglossal linkage. Anterior displacement of the soft palate servesto apply anterior and lateral (outward) tension to the lateralpharyngeal walls via the palatopharyngeal linkage as well as theinferior lateral pharyngeal walls via the pharyngoepiglottic linkage.

The anatomical linkage between the tongue base (genioglossus) and thelateral pharyngeal walls may be better appreciated with reference toFIG. 93. The anterior-inferior aspect (not visible) of the styloglossusmuscles insert into the genioglossus, and the posterior-superior aspectof the styloglossus muscles attach to the styloid process. Similarly,the anterior-inferior aspect (not visible) of the stylopharyngeusmuscles insert into the lateral pharyngeal walls, and theposterior-superior aspect of the stylopharyngeus muscles attach to thestyloid process. The glossopharyngeal aspects of the superior pharyngealconstrictor muscle also insert into the genioglossus. Thus, activationof the genioglossus serves to apply tension to the styloglossus and theglossopharyngeal aspects of the superior pharyngeal constrictor muscle,which in turn apply lateral outward tension to the lateral pharyngealwalls by virtue of the lateral outward position of the styloid processand the linkage via the stylopharyngeus muscles.

In sum, activation of the genioglossus muscle opens the retro-glossalairway as well as the retro-palatal airway via the linkages describedabove. In addition, activation of the genioglossus muscle serves to openthe lateral pharyngeal walls via the linkages described above. However,the linked effects on the soft palate and the lateral pharyngeal wallsis not present in all subjects but may be important for therapeuticsuccess of HGNS depending on the level and mode of collapse in a givenpatient. By using a tongue protrusion maneuver to mimic the effect onthe genioglossus muscle seen with HGNS, the response of the soft palateand lateral walls may be observed using endoscopy, for example. If thepalatal and lateral walls respond sufficiently to the tongue protrusionmaneuver, the likelihood of successful treatment with HGNS increases.Thus, observing the response of upper airway structures to the tongueprotrusion maneuver may be used as a screening tool prior toimplantation of a HGNS device.

Optionally, it may be desirable to observe the response of the airway atthe level of collapse. The level of collapse may be determined duringsleep or simulated sleep (e.g. sedation) using known techniques such asdrug induced sleep endoscopy (DISE), or may be determined by examinationof the airway structures using known techniques such as naso-endoscopy.The airway may collapse at the level of the tongue base (i.e.,retro-glossal), at the level of the palate (i.e. retro-palatal), or bothlevels. Because most OSA patients have palatal involvement in airwaycollapse, it may not be necessary to determine the level of collapse. Inthis case, collapse may be assumed to occur at least at the level of thepalate, and therefore an adequate response (e.g., increase in airwaysize) in the retro-palatal space during the tongue protrusion maneuverwould be indicative of likely therapeutic success with HGNS.

The principles of the present invention may be applied to othertherapeutic interventions for OSA involving the upper airway. Forexample, the tongue protrusion maneuver may be used as a screening toolfor surgery of the upper airway, such as uvulopalatopharyngoplasty(UPPP), palatal implants, genioglossus advancement, maxillo-mandibularadvancement, etc. Also, the tongue protrusion maneuver may be used as ascreening tool for oral appliances such as mandibular repositioningdevices, tongue retaining devices, etc.

Those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

Further aspects of the HGNS system 100 may be found in U.S. patentapplication Ser. No. 13/106,460, filed May 12, 2011, entitledOBSTRUCTIVE SLEEP APNEA TREATMENT DEVICES, SYSTEMS AND METHODS to Boleaet al., the entire disclosure of which is incorporated herein byreference.

Activation of the genioglossus muscle by HGNS causes anteriordisplacement of the tongue, thus opening the retro-glossal airway.Activation of the genioglossus muscle can also cause anteriordisplacement of the soft palate, thus opening the retro-palatal airwayspace. Activation of the genioglossus muscle can further cause lateraldisplacement of the lateral pharyngeal walls, thus further opening theupper airway. In this manner, activation of the genioglossus muscle byHGNS can mitigate different levels and modes of upper airway collapse inOSA subjects.

Although the effect of genioglossus activation on the tongue to open theretro-glossal airway is predictable given the mechanism of action, theeffect of genioglossus activation on the soft palate and lateral wallshas been heretofore poorly understood and variable across subjects.Nevertheless, in the majority of OSA patients, the soft palate and thelateral walls can contribute to upper airway collapse, alone or incombination with the tongue. Thus, to the extent that activation of thegenioglossus by HGNS does not fully mitigate upper airway collapse in agiven subject, adjunct therapies as described herein may be consideredto address other levels and modes of upper airway collapse, thuspotentially improving the subject's overall response to therapy.

The present disclosure provides a number of different therapies that maybe used adjunctively with another OSA therapy such as therapiestargeting the tongue (e.g., hypoglossal nerve stimulation,genioglossus-advancement, mandibular advancement surgery, mandibularadvancement oral appliances, etc.). Alternatively, the therapiesdescribed herein may be used as a stand-alone therapy for OSA and/orsnoring. To better understand the function of the therapies describedherein, it is helpful to consider the anatomical structures of the upperairway and the interactions of those structures.

With reference to FIGS. 90-94, the anatomical linkages between thetongue, soft palate and lateral walls may be explained in more detail.With specific reference to FIG. 94, the hypoglossal nerve (cranial nerveXII) innervates the genioglossus muscle, which is the largest upperairway dilator muscle. Activation of the genioglossus muscle viastimulation of the hypoglossal nerve causes tongue protrusion andanterior displacement of the soft palate, due to linkage via thepalatoglossal arch (muscle). Anterior displacement of the soft palate,in turn, can cause tension to be applied to the lateral pharyngeal wallsvia the palatopharyngeal arch (muscle). Thus, activation of thegenioglossus muscle causes opening of the upper airway at the level ofthe tongue base (retro-glossal space), at the level of the soft palate(retro-palatal space) via the palatoglossal arch, and along the lateralwalls via the palatopharyngeal arch.

The anatomical linkage between the tongue base (genioglossus) and thesoft palate via the palatoglossal arch, and the anatomical linkagebetween the soft palate and the lateral walls via the palatopharyngealarch may be more clearly seen in FIGS. 90 and 91. The palatoglossusmuscle forms the palatoglossal arch and the anterior-inferior aspect ofthe soft palate on either side of the uvula. The inferior and lateralends of the palatoglossus muscle insert into the genioglossus muscle.Posterior to the palatoglossal arch are the palatine tonsils, andposterior to the palatine tonsils is the palatopharyngeus muscle formingthe palatopharyngeal arch and the posterior-inferior aspect of the softpalate on either side of the uvula. The inferior and lateral ends of thepalatopharyngeus muscle insert into the lateral walls of the pharynx.

The inferior anatomical linkage between the soft palate and the lateralwalls via the pharyngoepiglottic fold may be more clearly seen in FIG.92. Activation of the genioglossus serves to pull the soft palateanteriorly via the palatoglossal linkage. Anterior displacement of thesoft palate serves to apply anterior and lateral (outward) tension tothe lateral pharyngeal walls via the palatopharyngeal linkage as well asthe inferior lateral pharyngeal walls via the pharyngoepiglotticlinkage.

The anatomical linkage between the tongue base (genioglossus) and thelateral pharyngeal walls may be better appreciated with reference toFIG. 93. The anterior-inferior aspect (not visible) of the styloglossusmuscles insert into the genioglossus, and the posterior-superior aspectof the styloglossus muscles attach to the styloid process. Similarly,the anterior-inferior aspect (not visible) of the stylopharyngeusmuscles insert into the lateral pharyngeal walls, and theposterior-superior aspect of the stylopharyngeus muscles attach to thestyloid process. The glossopharyngeal aspects of the superior pharyngealconstrictor muscle also insert into the genioglossus. Thus, activationof the genioglossus serves to apply tension to the styloglossus and theglossopharyngeal aspects of the superior pharyngeal constrictor muscle,which in turn apply lateral outward tension to the lateral pharyngealwalls by virtue of the lateral outward position of the styloid processand the linkage via the stylopharyngeus muscles.

The integrity and extent of the aforementioned linkages may vary acrosssubjects, and thus their response to HGNS therapy may vary accordingly.These linkages are significant because most people who snore or have OSAwill have some retro-palatal collapse with involvement of the palateand/or lateral walls. In these subjects, retro-palatal collapse may bedue to poor linkage (i.e., poor coupling) between the genioglossus andsoft palate, the soft palate and lateral walls, and/or the tongue andlateral walls, possibly the result of tissue redundancy (i.e., slack) inthe palatoglossus, palatopharyngeus, and/or pharyngoepiglottic fold,respectively. Tissue redundancy may also be present in the lateralpharyngeal walls due to adipose tissue (i.e., fat) at discrete locations(e.g., fat pads) or distributed throughout the pharyngeal walls,particularly in patients with high BMI, which is common in OSAsufferers.

By modifying these connective structures using the devices and methodsdescribed herein, the tendency of the tongue, soft palate, and/orlateral walls to collapse may be mitigated as an adjunct to HGNS therapyor as a stand-alone therapy to treat OSA and/or snoring. The connectivestructures may be modified using the devices and methods describedherein by changing their configuration and/or dimension (e.g.,shortening their length) and/or changing their mechanical properties(e.g., increasing their stiffness), for example. Although someembodiments are described with reference to a specific pharyngealstructure (e.g., palatoglossal tissue), the same embodiment may beapplied to other pharyngeal structures (e.g., palatopharyngeal tissue)in the alternative or in combination.

With reference to FIGS. 95A-95B, a method of shortening thepalatoglossal arch (PGA) is shown schematically. As seen in FIG. 95A,tissue is removed (cut or ablated) from the PGA to form a void 710limited to the palatoglossal muscle and surrounding mucosa while leavingthe rest of the soft palate unchanged. The amount and shape of thetissue removed may vary, to correspond to the amount of PGA shorteningdesired. In this example, a triangular notch 710 is formed symmetricallyon both sides of the PGA. Subsequently, the notches 710 are surgicallyclosed with sutures 712 or the like to bring the cut edges intoapproximation and thereby shorten the length of the PGA an amountapproximately equal to the sum of the bases of the triangular notches asseen in FIG. 95B. A triangular notch may be beneficial because itremoves more tissue from the inferior aspect of the PGA (base oftriangle) while minimizing tissue removal from the superior aspect ofthe PGA (apex of triangle), thus enabling shortening of the PGA whileminimizing disruption of the remainder of the soft palate. Thusshortening the length of the PGA applies tension to the soft palate andmoves it anteriorly relative to the tongue, thereby mitigatingretro-palatal collapse (OSA) and tissue vibration (snoring). Anyresultant scarring may serve to stiffen the respective tissue structuresthus enhancing the effect.

As an alternative, a plurality of tissue sections may be removed andclosed from both sides of the PGA as shown in FIG. 95C. In addition,although described with reference to the PGA, the same technique may beapplied to other pharyngeal connective structures either alone or incombination. For example, the same technique may be applied to thepalatopharyngeal arch (PPA) as shown in FIG. 95D and/or thepharyngoepiglottic fold (PEF) as shown in FIG. 95E. Also by way ofexample, this technique may be applied to a combination of pharyngealstructures such as the PGA and PPA as shown in FIG. 95F.

With reference to FIGS. 96A-96B, an alternative method of shorteningand/or stiffening the palatoglossal arch (PGA) is shown schematically.As seen in FIG. 96A, sutures 22 are bilaterally placed in the PGA in acrisscross fashion. The sutures 22 may generally follow the arcuateshape of the PGA and its width may be limited to the width of thepalatoglossal muscle and surrounding mucosa while leaving the rest ofthe soft palate unchanged. Once in place, the tags ends 24 of thesutures 22 may be pulled relative to the PGA as shown in FIG. 96B tocinch the adjacent tissue length-wise to thereby shorten the length ofthe PGA and/or stiffen the PGA. Optionally, tissue may be removed fromthe PGA prior to placement of the sutures 22 as described with referenceto FIG. 95A and elsewhere herein. The method described with reference toFIGS. 96A-96B may be applied to other pharyngeal structures in thealternative or in combination.

In some instances, it may be desirable to temporarily shorten or stiffenpharyngeal connective structures to determine if there is a positiveeffect (in terms of mitigating OSA and/or snoring) before performing anyof the permanent procedures described herein. To this end, and withreference to FIG. 97, placations 730 may be formed bilaterally in thePGA to shorten its length, and temporary holding devices 732 may beplaced across the placations 730 to retain the foreshortened length.Optionally, more than one placation 730 and holding device 732 may beplaced on each side of the PGA to adjust the foreshortened lengththereof. The holding device 732 may comprise, for example, a stud with aremovable end, similar to what is used for body piercing, such as anearring. With the PGA temporarily held in a foreshortened length, theeffect thereof may be studied while the patient is awake (e.g., by awakenasoendoscopy) and/or while the patient is asleep (e.g., drug inducedsleep endoscopy and/or, polysomnography). If a beneficial result (e.g.,enlarged airway, improved coupling, reduced snoring, and/or reduction inapneas and hypopneas) is observed in any of such studies, the temporaryholding device 732 may be removed and a permanent procedure as describedherein may be performed to have the same foreshortening and/orstiffening effect on the PGA. The method described with reference toFIG. 97 may be applied to other pharyngeal structures in the alternativeor in combination.

With reference to FIGS. 98A-98B, an alternative method of shortening thepalatoglossal arch (PGA) is shown schematically. As seen in FIG. 98A,tissue is removed (cut or ablated) from the PGA to form a circular void740 between the inferior and superior aspects of the PGA while leavingthe rest of the soft palate unchanged. The amount (diameter) removed mayvary, to correspond to the amount of PGA shortening desired. In thisexample, several circular holes are formed symmetrically on both sidesof the PGA. Subsequently, the holes 740 are surgically closed withsutures 742 or the like to bring the cut edges into approximation andthereby shorten the length of the PGA an amount approximately equal tothe sum of the diameters of the circular holes as seen in FIG. 98B. Acircular (or other shape) hole may be beneficial because it is confinedto the PGA between the inferior and superior aspects of the PGA. Themethod described with reference to FIGS. 98A-98B may be applied to otherpharyngeal structures in the alternative or in combination.

With reference to FIGS. 99A and 99B, a punch tool 750 is shown which maybe used to form the holes 740 shown in FIG. 98A. Punch tool 750 includesa handle 752 with an actuation lever 754 to advance a tubular punch 756through outer tube 757 to engage die 758. When lever 754 is squeezedrelative to handle 752, the punch 756 is advanced in outer tube 757.With die 758 fixed relative to outer tube 757, advancement of the punch756 as indicated by arrow 751 causes the distal cutting edge of thepunch 756 to press against the facing surface of the die 758. The tool750 may be positioned in the oral cavity with the PGA disposed betweenthe distal cutting edge of the punch 756 and the facing surface of thedie 758. When so positioned, the lever 754 may be actuated to advancethe die, pinch the PGA tissue between the punch 756 and die 758, andform a hole of any desired shape therein. This step may be repeated foreach additional hole to be formed in the PGA or other desired pharyngealtissue structure.

With reference to FIGS. 100A-100B, an alternative method of shorteningand/or stiffening the palatoglossal arch (PGA) is shown schematically.As seen in FIG. 100A, an insertion tool 770 may be used to implantdevices 760 bilaterally below the mucosa or in the muscle of the PGA asshown in FIG. 100B. The implant device 760 may comprise an elasticstructure having an elongated delivery configuration 760A and aforeshortened deployed configuration 760B as shown in FIGS. 101A and101B, respectively. The implant device 760 may comprise, for example,braided metal (e.g., stainless steel or super elastic nickel titaniumalloy) or braided elastomer (e.g., silicone) formed in a tubular shape,with an elongated state 760A and a relaxed state 760B. Thus, whenimplant device 760 is implanted submucosally in the PGA, the device 760expands diametrically to engage the surrounding tissue, and shortenslongitudinally to stiffen and/or shorten the length on the PGA. Multipleimplant devices 760 may be implanted in the PGA, and this method may beapplied to other pharyngeal structures in the alternative or incombination.

An alternative implant device 7160 is shown in FIGS. 101C-101G. In thisembodiment, implant device 7160 includes a shaft portion 7162 and twoanchors 7164. The implant device 7160 is placed into pharyngeal tissuein a first elongated state 7160A as shown in FIG. 101C, and subsequentlyassumes a second foreshortened state 7160B as shown in FIG. 101D. Tochange from the elongated state to the foreshortened state, a lengthchanging core 7166 may be disposed in the shaft portion 7162, withaccess thereto provided by a plurality of slots 7163 in the shaftportion 7162 as shown in FIG. 101E. The length changing member 7166 maycomprise a bio-resorbable material, a heat-shrink polymer that shortensupon application of heat, or a dissolvable material that dissolves uponexposure to a solvent (e.g., saline). The shaft portion 7162 and anchors7164 may comprise an elastic polymer material such as silicone.Initially, the shaft portion 7162 is stretched lengthwise and the core7166 is disposed therein to hold the shaft portion 7162 in a stretchedor elongated state. Post implantation, the core 7166 shortens (byresorbing, dissolving, or exposure to heat) causing the shaft portion7162 to shorten as it returns to its relaxed state. As the shaft 7162shortens, the anchors 7164 engage the surrounding tissue causing thetissue to foreshorten and stiffen. The anchors may comprise tines 7164as shown in FIG. 101E, a mesh 7164′ as shown in FIG. 101F, or a porousmaterial 7164″ as shown in FIG. 101G, wherein the mesh 7164′ and theporous material 7164″ promote tissue ingrowth for anchoring purposes.

To facilitate insertion of the implant device 760 or 7160 under themucosa or in the muscle of the PGA, an insertion tool 770 may be used asshown in FIGS. 102A and 102B. Insertion tool 770 includes a handle 772having a lever 774 that may be squeezed as indicated by arrow 773. Thelever 774 is mechanically coupled to a flexible outer tube 778, which isretractable relative to an inner member 776 that is fixed relative tohandle 772. The outer tube 778 includes a sharpened tip 779 forpenetrating into the mucosa and a distal opening for release of thedevice 760. The distal end of the inner member 776 abuts the proximalend of implant device 760. The outer tube 778 retains the implant device760 in an elongated, reduced diameter, delivery configuration 760A. Whenthe distal sharpened end of the outer tube 778 is placed under themucosa or in the muscle of the PGA, the outer tube 778 may be retractedas indicated by arrow 77 by actuation of lever 774 as indicated by arrow773, thereby releasing the implant device 760 in a shortened, increaseddiameter, deployed configuration 760B. Thus, the device 760 expands froman elongated delivery configuration 760A to a shortened deployedconfiguration 760B, thereby stiffening and/or shortening the length ofthe PGA. The insertion tool 770 may be used to delivery implant device760 or 7160 to other pharyngeal structures in the alternative or incombination.

With reference to FIGS. 103A-103B, an alternative method of shorteningand/or stiffening the palatoglossal arch (PGA) is shown schematically.As seen in FIG. 103A, an insertion tool 790 may be used to implantdevices 780 bilaterally below the mucosa or in the muscle of the PGA asshown in FIG. 103B. Prior to full insertion of the implant devices 780in the PGA, the PGA tissues are foreshortened using the insertion device790, for example, such that the implant devices 780 hold the PGA in aforeshortened state. The implant device 780 may comprise a semi-flexiblestructure that can flex laterally but resists elongation axially. Asshown in FIGS. 104A and 104B, the implant device 780 may include a shaftportion 782 with double-barbed anchors 784 at opposite ends of the shaftportion 782. Alternatively, as shown in FIGS. 104C and 104D, the implantdevice 780 may include a shaft portion 782 with single-barbed anchors786 at opposite ends of the shaft portion 782. Anchors 784 and 786 mayhave a low profile delivery configuration 784A and 786A, and an expandeddeployed configuration 784B and 786B, as shown. The anchors 784 and 786are unidirectional such that they can be easily inserted into tissue inone direction but resist withdraw in the other (opposite) direction. Foreach implant device 780, the unidirectional characteristic of eachanchor is opposite, such that the anchor 784/786 on a first end of theshaft 782 is unidirectional in a first direction, and the anchor 784/786on the second end of the shaft 782 is unidirectional in a seconddirection opposite from the first direction. This arrangement of theanchors 784/786 allows tissues surrounding the implant device 780 toforeshorten along the shaft portion 782 while holding the tissues in aforeshortened state to shorten the length of the PGA. The implant device780 may comprise, for example, an implantable grade permanent polymer, abio-resorbable polymer (e.g., PLLA, PGA), etc. Multiple implant devices780 may be implanted in the PGA, and this method may be applied to otherpharyngeal structures in the alternative or in combination.

To facilitate insertion of the implant device 780 under the mucosa or inthe muscle of the PGA, an insertion tool 790 may be used as shown inFIGS. 105A-105D. Insertion tool 790 includes an inner push member 792,an outer push tube 796, and an intermediate tube 794 with a sharpeneddistal end. Initially, the intermediate tube 794 extends distally beyondthe inner push member 792 and the outer push tube 796, with the implantdevice 780 contained in tube 794 in a delivery configuration with theanchors 784 folded in. In this configuration, all components 792, 794,796 of the insertion tool 790 are advanced distally in unison asindicated by arrows A, B, C, and the intermediate tube 794 is insertedinto the tissue as shown in FIG. 105A. Once the intermediate tube 794containing the implant device 780 is advanced sufficiently into thetarget tissue, the inner push member 792 is advanced distally as shownby arrow A, while the intermediate tube 794 and outer tube 796 remainstationary, thus pushing the implant device 780 out of the distal end ofthe intermediate tube 794 to deploy distal anchor 784 as shown in FIG.105B. The outer push tube 796 is advanced distally as shown by arrow C,while the inner push member 792 and the intermediate tube 794 remainstationary, thus engaging the distal flared end of the outer tube 796against the target tissue causing it to foreshorten as shown in FIG.105C. The intermediate tube 794 is then withdrawn proximally as shown byarrow B, while the inner push member 792 and outer push tube 796 remainstationary, thus deploying the proximal anchor 784 of the implant device780 to hold the tissue in a foreshortened state as shown in FIG. 105D.The insertion tool 790 may be used to delivery device 780 to otherpharyngeal structures in the alternative or in combination.

An alternative insertion tool 7190 may be used to facilitate insertionof the implant device 780 under the mucosa or in the muscle of the PGAas shown in FIGS. 106A-106D. Insertion tool 7190 includes an inner pushmember 7192, an outer push tube 7196, and an intermediate tube 7194. Theintermediate tube 7194 includes a sharpened tip 7195 and a bulb portion7193 having an enlarged diameter. The outer tube 7196 includes a slotteddistal end defining a plurality of finger-like projections 7197 thatextend outward when advanced over the bulb portion 7193 of theintermediate tube 7194. Initially, the intermediate tube 7194 extendsdistally beyond the inner push member 7192 and the outer push tube 7196,with the implant device 780 contained in the intermediate tube 7194 in adelivery configuration with the anchors folded in. In thisconfiguration, all components 7192, 7194, 7196 of the insertion tool7190 are advanced distally in unison, and the intermediate tube 7194 isinserted into the tissue. Once the intermediate tube 7194 containing theimplant device 780 is advanced sufficiently into the target tissue, theinner push member 7192 is advanced distally as shown by arrow A, whilethe intermediate tube 7194 and outer tube 7196 remain stationary, thuspushing the implant device 780 out of the distal end of the intermediatetube 7194 to deploy the distal anchor of the implant device 780 as shownin FIG. 106A. The outer push tube 7196 is advanced distally as shown byarrow B, while the inner push member 7192 and the intermediate tube 7194remain stationary, thus engaging the finger-like projections 7197 of theouter tube 7196 against the bulb portion 7193 of the intermediate tube7194 and causing the fingers to flare outward. The flared projections7197 then push against the target tissue causing it to foreshorten asshown in FIG. 106B. The intermediate tube 7194 is then withdrawnproximally as shown by arrow C, while the inner push member 7192 andouter push tube 7196 remain stationary, thus deploying the proximalanchor of the implant device 780 to hold the tissue in a foreshortenedstate as shown in FIG. 106C. The insertion tool 7190 may then be removedfrom the target tissue leaving the implant device in place as shown inFIG. 106D. The insertion tool 7190 may be used to delivery device 780 toother pharyngeal structures in the alternative or in combination.

With reference to FIGS. 107A-107F, various implant devices are shownschematically which, in general, improve coupling between the tongue andthe soft palate via the palatoglossal arch. In FIGS. 107A and 107B, twoimplant devices 410 extend from the soft palate, through thepalatoglossal arch and into the genioglossus. Each implant device 410includes a tether member 412 (e.g., multi-filament polymer), and twotissue anchors (e.g., polymer barb) 414 and 416 residing in thegenioglossus and soft palate, respectively. The implant devices 410 maybe implanted using insertion tool 790 for example, such that it appliestension between the soft palate and tongue via the palatoglossal arch,thereby improving coupling therebetween. In FIG. 107C, a variation ofimplant device 410 is shown as implant device 7420, which functions in asimilar manner but eliminates tissue anchors in the tongue in favor aloop of the tether 412.

In FIGS. 107D-107E, two implant devices 7430 extend from the softpalate, through the palatoglossal arch and genioglossus, to themandible. In this embodiment, device 7430 includes a tether member 412,a tissue anchor 416 residing in the soft palate, and a bone anchor 418residing in the mandible. The implant devices 7430 may be implantedusing insertion tool 790 for example, such that it applies tensionbetween the soft palate and tongue via the palatoglossal arch, therebyimproving coupling therebetween. In FIG. 107F, a variation of implantdevice 7430 is shown as implant device 7440, which functions in asimilar manner but eliminates tissue anchors in the palate in favor aloop of the tether 412.

With reference to FIGS. 108A-108D, a palatal appliance 510 is shownschematically. As seen in the side view shown in FIG. 108A and the frontview shown in FIG. 108B, the palatal appliance 510 includes a dentitionportion 512, a palatal portion 514, and a connecting arch member 516. Asshown in FIGS. 108C and 108D, the dentition portion 512 engages thefront teeth, the palatal portion 514 includes two tabs that engage theposterior aspect of the soft palate on either side of the uvula, and thearch member 516 extends along the roof of the mouth to connect thedentition portion 512 to the palatal portion 514. The palatal appliance510 may be formed of conventional materials used for dental appliances,and may be customized for an individual patient using a boil-and-bitetechnique or a mold-and-thermoform technique. In use, the palatalappliance 510 keeps the soft palate from falling posteriorly, and may beunder-sized to displace the soft palate anteriorly from its normalposition. Palatal appliance 510 may be used as a stand-alone therapy inthe case of isolated retro-palatal collapse, or used as an adjunct toHGNS therapy in the case of poor palatal coupling.

With reference to FIG. 109, an oral appliance 520 is shownschematically. The oral appliance 520 includes upper and lower dentitionportions 522A and 522B, and a spacer portion 524. The dentition portions522A and 522B engage the teeth, and the spacer 524 resides between theupper and lower teeth as well as the upper and lower lips. An archmember (not shown) may be provided to extend from the spacer along theroof of the mouth. The spacer portion 524 includes a middle portion 526and two lateral portions 528. The middle portion 526 defines a lumen 527through which air may flow freely, or into which the tongue may extend(if used in conjunction with HGNS therapy). Similarly, the lateralportions 528 define lumens 529 through which air may flow freely. Thelateral portions 528 may include baffles 7530 in a serpentine shape, forexample, to provide structural support while permitting airflowtherethrough. The arch portion (not shown) may also include a flow pathin communication with lumens 527 and 529 through which air may flowfreely. The dentition portions 522A and 522B secure the appliance 520 inthe mouth during sleep, but permits easy insertion and removal of theappliance 520 to/from the oral cavity at the beginning and ending of thesleep period, respectively. Optionally, one dentition portion 522A or522B may be used. The spacer 524 keeps the mouth open (teeth and lips)to permit mouth breathing, despite the tendency of the mouth to closeduring sleep. Similarly, the arch portion maintains a flow path formouth breathing, despite the tendency of the tongue to fall against theroof of the mouth during sleep. The spacer 524 may have a rectangularhousing with a serpentine support baffle 7530 as shown, or theserpentine support structure 7530 without a housing. The oral appliance520 may be formed of conventional materials used for dental appliances,and may be customized for an individual patient using a boil-and-bitetechnique or a mold-and-thermoform technique. In use, the oral appliance520 maintains an open flow path for mouth breathing, despite thetendency of the mouth to close and the tongue to rest against the roofof the mouth during sleep. Oral appliance 520 may be used as astand-alone therapy in the case of isolated retro-palatal collapse, orused as an adjunct to HGNS therapy in the case of poor palatal coupling.

The adjunct devices and therapies described herein may be used incombination with HGNS therapy, or other therapeutic interventions thatdirectly address retro-glossal collapse. For example, the adjuncttherapies described herein may be used in combination with genioglossusadvancement surgery, mandibular advancement surgery, mandibularadvancement (oral) appliances, etc. Alternatively, the therapiesdescribed herein may be used as stand-alone procedures to treat OSAand/or snoring.

Examples of conventional OSA therapies that may be used as an adjunct toHGNS include palate surgeries such as uvulopalatopharyngoplasty (UPPP),palatopharyngoplasty, uvulopalatal flap, and palatal implants (e.g.,Pillar® implants sold by Medtronic). Palate surgeries primarily affectupper airway collapse at the level of the palate. As such, thesetherapies may be considered as adjunct to HGNS in subjects that haveresidual retro-palatal collapse with HGNS therapy, possibly due to pooranatomical coupling between the tongue and the palate.

From the foregoing, it will be apparent to those skilled in the art thatthe present disclosure provides, in non-limiting embodiments, devicesand methods for treating OSA and snoring by modifying pharyngeal tissueof the upper airway such as, e.g., the palatoglossus, palatopharyngeus,pharyngeoepiglottis, and/or lateral walls. Further, those skilled in theart will recognize that the present disclosure may be manifested in avariety of forms other than the specific embodiments described andcontemplated herein. Accordingly, departures in form and detail may bemade without departing from the scope and spirit of the presentdisclosure as described in the appended claims.

The present disclosure also relates to a method of providing hypoglossalnerve stimulation therapy to a patient for the treatment of obstructivesleep apnea, comprising: performing an assessment of the patient,wherein the assessment comprises protruding the patient's tongue andobserving a response of the patient's upper airway; and implanting ahypoglossal nerve stimulation device in the patient only if the responsecomprises an increase in airway size, wherein implanting the hypoglossalnerve stimulation device comprises implanting a neurostimulator and astimulation delivery lead in the patient; titrating stimulation settingsof the neurostimulator while the patient is awake; and titratingstimulation settings of the neurostimulator while the patient is asleep.In at least one embodiment, the upper airway may be observed while thepatient is awake and supine. The tongue protrusion may be volitional.The upper airway may be observed by endoscopy. The increase in airwaysize may be at least one of retro-glossal and retro-palatal. Theincrease in airway size may comprise an increase in one of ananterior-posterior dimension and a lateral dimension. The assessment mayfurther comprise determining a level of collapse in the patient's upperairway. In at least one embodiment, the patient is treated with thetherapy only if the response of the upper airway is an increase in size,and only if another response is observed during tongue protrusion. In atleast one embodiment, the method further comprises delivering anelectrical stimulation to the hypoglossal nerve, wherein the electricalstimulation is triggered as a function of aspiration onset. Thestimulation delivery lead may include a distal end coupled to a nervecuff including a plurality of electrodes configured to steer anelectrical field.

The present disclosure further relates to a method of treatingobstructive sleep apnea, comprising: chronically implanting an electrodeon a hypoglossal nerve at a site to stimulate a tongue protrude muscleand a tongue retruder muscle; and periodically delivering a stimulus tothe nerve via the electrode to mitigate obstruction of the upper airway,wherein the stimulus is configured to selectively activate the tongueprotrude muscle more than or before the tongue retruder muscle, andfurther wherein the stimulus is delivered if an inspiratory phase of arespiratory cycle is at least 40% of the respiratory cycle. The stimulusmay be triggered based on a sensed parameter indicative of respiration.In some embodiments, the sensed parameter may be impedance. Electricalfield steering may be used for selective activation.

The foregoing embodiments, which are non-limiting, may be combined inways beyond those specifically described herein.

I claim:
 1. A method of treating a patient, comprising: sensing, bycircuitry, a biological parameter indicative of respiration; analyzing,by the circuitry, the biological parameter to identify a respiratorycycle; identifying, by the circuitry, an inspiratory phase of therespiratory cycle; determining, by the circuitry, that a duration of theinspiratory phase of the respiratory cycle is at least a predeterminedpercentage of a duration of the entire respiratory cycle; anddelivering, by the circuitry, stimulation generated by a generator to ahypoglossal nerve of the patient via a lead coupled to the generator inresponse to determining the duration of the inspiratory phase of therespiratory cycle is at least the predetermined percentage of theduration of the entire respiratory cycle; wherein the predeterminedpercentage of the duration of the entire respiratory cycle is at least25% of the duration of the entire respiratory cycle.
 2. The method ofclaim 1, wherein the predetermined percentage of the duration of theentire respiratory cycle is at least 40% of the duration of the entirerespiratory cycle.
 3. The method of claim 1, wherein the biologicalparameter includes impedance.
 4. The method of claim 3, whereinanalyzing the biological parameter to identify a respiratory cycleincludes identifying impedance peaks.
 5. The method of claim 4, furthercomprising comparing an amplitude of the impedance peaks to a threshold.6. The method of claim 1, wherein the predetermined percentage of theduration of the entire respiratory cycle is at least 50% of the durationof the entire respiratory cycle.
 7. An implantable medical device,comprising: circuitry configured to: sense a biological parameterindicative of respiration of a patient; analyze the biological parameterto identify a respiratory cycle; identify an inspiratory phase of therespiratory cycle; determine that a duration of the inspiratory phase ofthe respiratory cycle is at least a predetermined percentage of aduration of the entire respiratory cycle; and deliver stimulationgenerated by a generator to a hypoglossal nerve of the patient via alead coupled to the generator in response to determining the duration ofthe inspiratory phase of the respiratory cycle is at least thepredetermined percentage of the duration of the entire respiratorycycle; wherein the predetermined percentage of the duration of theentire respiratory cycle is at least 25% of the duration of the entirerespiratory cycle.
 8. The device of claim 7, wherein the predeterminedpercentage of the duration of the entire respiratory cycle is at least40% of the duration of the entire respiratory cycle.
 9. The device ofclaim 7, wherein the biological parameter includes impedance.
 10. Thedevice of claim 9, wherein analyzing the biological parameter toidentify a respiratory cycle includes identifying impedance peaks. 11.The device of claim 10, wherein the circuitry is further configured tocompare an amplitude of the impedance peaks to a threshold.
 12. Thedevice of claim 7, wherein the predetermined percentage of the durationof the entire respiratory cycle is at least 50% of the duration of theentire respiratory cycle.
 13. An implantable medical device, comprising:a lead; a generator coupled to the lead that generates stimulation to beprovided to the lead; and circuitry coupled to the generator, whereinthe circuitry is configured to: sense a biological parameter indicativeof respiration of a patient; analyze the biological parameter toidentify a respiratory cycle; identify an inspiratory phase of therespiratory cycle; determine that a duration of the inspiratory phase ofthe respiratory cycle is at least a predetermined percentage of aduration of the entire respiratory cycle; and deliver stimulationgenerated by the generator to a hypoglossal nerve of the patient via thelead coupled to the generator in response to determining the duration ofthe inspiratory phase of the respiratory cycle is at least thepredetermined percentage of the duration of the entire respiratorycycle; wherein the predetermined percentage of the duration of theentire respiratory cycle is at least 50% of the duration of the entirerespiratory cycle.
 14. The device of claim 13, wherein the predeterminedpercentage of the duration of the entire respiratory cycle is at least40% of the duration of the entire respiratory cycle.
 15. The device ofclaim 13, wherein the biological parameter includes impedance.
 16. Thedevice of claim 15, wherein analyzing the biological parameter toidentify a respiratory cycle includes identifying impedance peaks. 17.The device of claim 16, wherein the circuitry is further configured tocompare an amplitude of the impedance peaks to a threshold.